12-120996568-C-G

Position:

chr12-120996568-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BA1

This summary comes from the ClinGen Evidence Repository: The c.1135C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to alanine at codon 379 (p.(Pro379Ala)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While this variant has been identified in >20 unrelated individuals with diabetes in the literature (ClinVar ID 431970, PMID:18003757, PMID:23348805, PMID:29207974, PMID:21761282, PMID:23607861), it has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005091, which is greater than the MDEP threshold for BA1 (greater than 0.0001) (BA1). Therefore, PS4 cannot be applied. While another variant at this codon, c.1136C>G (p.(Pro379Arg)), is classified as Pathogenic by the MDEP, the c.1135C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): BA1, PP3. It may, however, confer an increased risk of type 2 diabetes (OR = 11.8, p = 0.0007324 at type2diabetesgenetics.org). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831955/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:4U:6B:4

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

HNF1A links:

HNF1A (HGNC:):

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8 linkuse as main transcript	c.1135C>G	p.Pro379Ala	missense_variant	6/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 linkuse as main transcript	c.1135C>G	p.Pro379Ala	missense_variant	6/10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 linkuse as main transcript	c.1135C>G	p.Pro379Ala	missense_variant	6/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.1135C>G	p.Pro379Ala	missense_variant	6/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1135C>G	p.Pro379Ala	missense_variant	6/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000188

AC:

AN:

250080

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

180

AN:

1461638

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000112

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000251

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Pathogenic:4Uncertain:6Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 3

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace proline with alanine at codon 379 of the HNF1A protein, p.(Pro379Ala). The proline residue is highly conserved (100 vertebrates, UCSC), and there is a small physicochemical difference between proline and alanine. The variant is present in a large population cohort that incorporates multiple type 2 diabetes studies at a global frequency of 0.02% (rs754729248, 52/281432 alleles, 1 homozygote in gnomAD v2.1.1), and at 0.06% in the Latino population. It is present at a similar frequency of 0.02% (18/119738 alleles, 0 homozygotes) in the global gnomAD control cohort, but a reduced frequency of 0.03% in the controls of Latino background. This variant has been found in multiple cases diagnosed with different forms of diabetes including MODY3 (PMID: 18003757, 23348805, 23139355, 29207974, 30202817, 31485449), and is classified as likely pathogenic/pathogenic (ClinVar ID: 431970). Although the variant is more common in the population than expected for dominant disease, the prevalence of the variant in a MODY3 cohort (8/356, PMID: 18003757) is significantly increased compared with the prevalence in gnomAD controls. Additionally, this variant is present within small cohorts of HNF1A-MODY cases with significantly increased haemoglobin A1c and fasting glucose levels, and bile acid synthesis compared to healthy controls (PMID: 23139355, 23607861). The variant is located in the transactivation domain (PMID: 18003757), and functional studies have shown that Pro379Ala significantly increases activation of the CYP7A1 promoter compared to wild-type (PMID: 23607861). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Furthermore, four alternative missense changes at this position have been seen before in MODY3 cases (p.Pro379Thr, p.Pro379Ser, p.Pro379Arg, p.Pro379His; PMID: 18003757, 16917892). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4, PS3_Supporting, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Different missense changes at the same codon have been reported to be associated with HNF1A related disorder (PMID:18003757,18003757,15883474,15657605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.964>=0.6). A missense variant is a common mechanism . It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of 0.000188. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Pro379Ala variant in HNF1A has been reported in 8 individuals with maturity-onset diabetes of the young type 3 (PMID: 19754856, 29207974, 23607861, 30202817, 30155490, 2176128) and has been Identified in 0.07914% (28/35382) of Latino chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754729248). This variant has also been reported in ClinVar (VariationID: 431970) as likely pathogenic by GeneDx and as pathogenic by Fulgent Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Pro379Ala have been reported in association with disease in the literature, suggesting that this variant is in a mutational hot spot and supports pathogenicity (PMID: 23348805, 16917892). Three additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro379Thr, p.Pro379Arg, and p.Pro379His, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23348805, 16917892, 29666556, 15657605, 15883474, 30293189, 21683639, 26479152, 28012402). In summary the clinical significance of the p.Pro379Ala variant is uncertain. ACMG/AMP Criteria applied: BA1, PS4_moderate, PM1, PM5, PP3, (Richards 2015). -

not provided

Pathogenic:1Uncertain:2Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2024	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 379 of the HNF1A protein (p.Pro379Ala). This variant is present in population databases (rs754729248, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 18003757, 31264968). ClinVar contains an entry for this variant (Variation ID: 431970). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function. Experimental studies have shown that this missense change affects HNF1A function (PMID: 23607861). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Pro379Ala variant in HNF1A has been reported in at least 14 individuals with maturity-onset diabetes of the young, 1 individual with type 1 diabetes and 1 individual with type 2 diabetes (Cervin 2010 PMID: 19754856, Ekholm 2013 23607861, Huang 2018 30155490, Bellanné-Chantelot 2008 PMID: 18003757, Yu 2019 PMID: 31264968, Kleinberger 2017 PMID: 29758564), but it has also been identified in 0.08% (28/35382) of Latino chromosomes by the gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (VariationID: 431970). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Pro379Ala have been reported in association with disease in the literature, suggesting that this variant is in a mutational hot spot and additional variants involving this codon (p.Pro379Thr, p.Pro379Arg, and p.Pro379His) have been reported in individuals with monogenic diabetes supporting that a change at this position may not be tolerated. In summary, due to conflicting data, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting, PM1, PM5, PP3. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2023	Variant summary: HNF1A c.1135C>G (p.Pro379Ala) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 281432 control chromosomes (gnomAD), predominantly at a frequency of 0.00079 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 32 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 (2.5e-05) (MODY3), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1135C>G has been reported in the literature in individuals affected with Diabetes without evidence of familial inheritance and/or clinical features of HNF1A-associated MODY3 (e.g. Bellanne-Chantelot_2008, Ekholm_2013, Bansal_2017, Huang_2018, Kleinberger_2018, Yu_2019). These reports do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. One publication reports that the variant had increased induction of the CYP7A1 promotor when transiently transfected into HuH7 cells, but had no effects of the activation or repression of other promotors in HuH7 or Caco2 cells (Ekholm_2013), suggesting the variant may not cause loss of function. The following publications have been ascertained in the context of this evaluation (PMID: 29207974, 18003757, 23607861, 30155490, 29758564, 31264968). Multiple submitters, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (EP as benign, n=1; VUS, n=7; P/LP, n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Type 2 diabetes mellitus

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The p.P379A variant (also known as c.1135C>G), located in coding exon 6 of the HNF1A gene, results from a C to G substitution at nucleotide position 1135. The proline at codon 379 is replaced by alanine, an amino acid with highly similar properties. This variant was identified in multiple families suspected of having maturity-onset diabetes of the young (Bellanné-Chantelot C et al. Diabetes, 2008 Feb;57:503-8; Ekholm E et al. Acta Diabetol, 2012 Oct;49:349-54; Colclough K et al. Hum. Mutat., 2013 May;34:669-85; Bansal V et al. BMC Med, 2017 Dec;15:213). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Monogenic diabetes

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Sep 06, 2023

The c.1135C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to alanine at codon 379 (p.(Pro379Ala)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While this variant has been identified in >20 unrelated individuals with diabetes in the literature (ClinVar ID 431970, PMID:18003757, PMID: 23348805, PMID: 29207974, PMID: 21761282, PMID: 23607861), it has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005091, which is greater than the MDEP threshold for BA1 (greater than 0.0001) (BA1). Therefore, PS4 cannot be applied. While another variant at this codon, c.1136C>G (p.(Pro379Arg)), is classified as Pathogenic by the MDEP, the c.1135C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): BA1, PP3. It may, however, confer an increased risk of type 2 diabetes (OR = 11.8, p = 0.0007324 at type2diabetesgenetics.org). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.2

D;.;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.88

MutPred

0.93

Loss of catalytic residue at P378 (P = 0.0116);Loss of catalytic residue at P378 (P = 0.0116);Loss of catalytic residue at P378 (P = 0.0116);Loss of catalytic residue at P378 (P = 0.0116);

MVP

0.98

MPC

0.56

ClinPred

0.66

GERP RS

4.6

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over