rs137853247

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. BA1BS3_SupportingPM1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.92G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 31 (p.(Gly31Asp)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). While it has been noted to be a pathogenic variant in the literature, there are numerous pieces of evidence that refute this classification. Functional studies demonstrated the p.Gly31Asp protein has DNA binding above 75% of wild type, indicating that this variant does not impact protein function (PMID:32910913) (BS3_Supporting). This variant has a REVEL score of 0.591, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function. The variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000772 (0.0772%), which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). It has been was identified in >30 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:31365591, 31638168, 19169489, 26431509, 28395978, 20950394, 26059258, 19929997, 22432108, 27899486, 23551881, 24041679, 16917892, 21696527, and others). In summary, c.92G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): BA1, BS3_Supporting, PM1_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA124487/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 3 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:4U:3B:11

Conservation

PhyloP100: 3.06

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 -8 ACMG points.

PM1

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

BS3

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.92G>A	p.Gly31Asp	missense_variant	1/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 linkuse as main transcript	c.92G>A	p.Gly31Asp	missense_variant	1/10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 linkuse as main transcript	c.92G>A	p.Gly31Asp	missense_variant	1/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.92G>A	p.Gly31Asp	missense_variant	1/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.92G>A	p.Gly31Asp	missense_variant	1/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.000782

AC:

119

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

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:

0.00109

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000772

AC:

192

AN:

248682

Hom.:

AF XY:

0.000703

AC XY:

AN XY:

135122

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000888

AC:

1298

AN:

1461178

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

625

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.000781

AC:

119

AN:

152296

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000625

Hom.:

Bravo

AF:

0.000861

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000692

AC:

ClinVar

Significance: Benign

Submissions summary: Pathogenic:4Uncertain:3Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2024	Variant summary: HNF1A c.92G>A (p.Gly31Asp) results in a non-conservative amino acid change located in the HNF-1, dimerization domain (IPR044866) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 1613474 control chromosomes, predominantly at a frequency of 0.0017 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 68 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05). c.92G>A has been reported in the literature in individuals affected with HNF1A-related conditions (examples: Urruitia_2019, Johnson_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 32910913, 31365591, 30191644). ClinVar contains an entry for this variant (Variation ID: 14948). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Gly31Asp variant in HNF1A is classified as likely benign because it has also been identified in 0.16% (55/35352) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org; dbSNP rs137853247). This variant has also been reported in ClinVar (Variation ID 29987). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. ACMG/AMP criteria applied: BS1. -

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	HNF1A: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 26, 2019	- -

Maturity-onset diabetes of the young type 3

Pathogenic:1Benign:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Maturity onset diabetes mellitus in young

Pathogenic:1Benign:1

Likely pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs137853247 with MODY3. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 15, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Clear cell carcinoma of kidney

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Chromophobe renal cell carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

HNF1A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2024

The HNF1A c.92G>A variant is predicted to result in the amino acid substitution p.Gly31Asp. This variant has been repeatedly reported in patients with maturity onset diabetes of the young (MODY), but its pathogenicity is still inconclusive (Chèvre et al. 1998. PubMed ID: 9754819; Beijers et al. 2009. PubMed ID: 19929997; Thanabalasingham et al. 2012. PubMed ID: 22432108). This variant could be pathogenic but a decreased penetrance may occur (Thanabalasingham et al. 2012. PubMed ID: 22432108). This variant is reported in 0.16% of alleles in individuals of Latino descent in gnomAD, including one homozygous observation. Of note, at PreventionGenetics, the HNF1A c.92G>A (p.Gly31Asp) variant has been observed in an individual with MODY heterozygous for a pathogenic GCK variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

Monogenic diabetes

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Dec 15, 2021

The c.92G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 31 (p.(Gly31Asp)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). While it has been noted to be a pathogenic variant in the literature, there are numerous pieces of evidence that refute this classification. Functional studies demonstrated the p.Gly31Asp protein has DNA binding above 75% of wild type, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant has a REVEL score of 0.591, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function. The variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000772 (0.0772%), which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). It has been was identified in >30 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 31365591, 31638168, 19169489, 26431509, 28395978, 20950394, 26059258, 19929997, 22432108, 27899486, 23551881, 24041679, 16917892, 21696527, and others). In summary, c.92G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): BA1, BS3_Supporting, PM1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.49

.;T;T;T;T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.84

T;T;T;T;T;T

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.044

T;T;T;T;T;T

MetaSVM

Uncertain

0.30

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.55

N;.;.;.;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.39

T;.;.;.;T;T

Sift4G

Benign

0.48

T;T;T;T;T;T

Polyphen

0.017

.;.;.;.;.;B

Vest4

0.57

MVP

0.98

MPC

0.66

ClinPred

0.012

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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