12-120978797-C-T

Position:

chr12-120978797-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1_SupportingPM5_SupportingPP4

This summary comes from the ClinGen Evidence Repository: The c.29C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 10 (p.(Thr10Met)) of NM_000545.8. This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  Additionally, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). While the variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate could not be applied because c.29C>T does not meet the criteria to apply PM2_Supporting (≤0.00002 allele frequency in the European Non-Finnish population and ≤1 copy in any other subpopulation)(PMIDs 30155490, 18003757, internal lab contributors). Another missense variant, c.28A>C (p.Thr10Pro) has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PP4, PM5_Suppporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831654/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

HNF1A
ENST00000257555.11 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:5

Conservation

PhyloP100: 2.46

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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

HNF1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

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

PM5

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

PP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HNF1A	NM_000545.8 linkuse as main transcript	c.29C>T	p.Thr10Met	missense_variant	1/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.29C>T	p.Thr10Met	missense_variant	1/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.29C>T	p.Thr10Met	missense_variant	1/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.29C>T	p.Thr10Met	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.29C>T	p.Thr10Met	missense_variant	1/10	1	NM_000545.8	ENSP00000257555	P4
HNF1A-AS1	ENST00000619441.1 linkuse as main transcript	n.128+1847G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247688

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134830

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460818

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 3

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 13, 2015	- -
Uncertain significance, 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. 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. -

Monogenic diabetes

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Mar 28, 2022	The c.29C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 10 (p.(Thr10Met)) of NM_000545.8. This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). While the variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate could not be applied because c.29C>T does not meet the criteria to apply PM2_Supporting (>=0.00002 allele frequency in the European Non-Finnish population and >=1 copy in any other subpopulation)(PMIDs 30155490, 18003757, internal lab contributors). Another missense variant, c.28A>C (p.Thr10Pro) has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PP4, PM5_Suppporting. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Thr10Met variant in HNF1A has been reported in at least 3 individuals with Monogenic Diabetes (PMID: 16917892, 18003757, 28938416), and has been identified in 0.01290% (2/15504) of African chromosomes, 0.005794% (2/34520) of Latino chromosomes, and 0.005473% (1/18270) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs774637975). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr10Met variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting (Richards 2015). -

Maturity onset diabetes mellitus in young

Pathogenic: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 rs774637975 with MODY3. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2023

Identified in a patients with suspected MODY in published literature, however, clinical information was limited in some cases and was not sufficient for a diagnosis of HNF1A-related MODY in other cases (PMID: 16917892, 30155490, 18003757, 28938416); Published functional studies are discordant regarding the pathogenicity of this variant (PMID: 32910913, 27083284); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29758564, 32238361, 31485449, 32910913, 30155490, 18003757, 33046911, 28938416, 36208030, 27083284, 16917892, 23348805) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.56

.;D;T;D;T;.

Eigen

Benign

-0.049

Eigen_PC

Benign

0.011

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.40

T;T;T;T;T;T

MetaSVM

Uncertain

0.46

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.79

N;.;.;.;N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.023

D;.;.;.;D;D

Sift4G

Uncertain

0.047

D;D;T;D;T;D

Polyphen

0.96

.;.;.;.;.;D

Vest4

0.25

MVP

0.97

MPC

0.17

ClinPred

0.56

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.58

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