rs483353044

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.1522G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 508 (p.(Glu508Lys)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.002884, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). This variant has been found in many unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PMID:24915262); however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting. Functional studies demonstrated the p.Glu508Lys protein has transactivation activity between 40-80%, which is less severe than typical HNF1A-MODY-causing variants (below 40%) (PMID:32910913, 27899486). In summary, this variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: BA1 (specification version 1.2, approved 6/5/21). However, this variant is an established risk allele for type 2 diabetes in individuals of Mexican ancestry (PMID:24915262). These individuals do not respond to treatment with sulfonylureas, unlike individuals with HNF1A-MODY (PMID:29844095). LINK:https://erepo.genome.network/evrepo/ui/classification/CA289173/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:6O:1

Conservation

PhyloP100: 9.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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.1522G>A	p.Glu508Lys	missense_variant	8/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 linkuse as main transcript	c.1522G>A	p.Glu508Lys	missense_variant	8/10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 linkuse as main transcript	c.1330G>A	p.Glu444Lys	missense_variant	7/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.1522G>A	p.Glu508Lys	missense_variant	8/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1522G>A	p.Glu508Lys	missense_variant	8/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000486

AC:

122

AN:

251000

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00338

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1461714

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

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

Bravo

AF:

0.000162

ExAC

AF:

0.000436

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 31, 2023	Variant summary: HNF1A c.1522G>A (p.Glu508Lys) results in a conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251600 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 19 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), strongly suggesting that the variant is benign. c.1522G>A has been reported in the literature as a non-significant risk factor in association with Type 2 diabetes (95% CI overlaps 1) (example, Estrada_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. Four clinical diagnostic laboratories and an expert panel (ClinGen Monogenic Diabetes Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (B/LB, n=3 including the expert panel; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2021	- -

Maturity-onset diabetes of the young type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Maturity onset diabetes mellitus in young

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

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. -

Monogenic diabetes

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Dec 01, 2022

The c.1522G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 508 (p.(Glu508Lys)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.002884, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). This variant has been found in many unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PMID: 24915262); however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting. Functional studies demonstrated the p.Glu508Lys protein has transactivation activity between 40-80%, which is less severe than typical HNF1A-MODY-causing variants (below 40%) (PMID: 32910913, 27899486). In summary, this variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: BA1 (specification version 1.2, approved 6/5/21). However, this variant is an established risk allele for type 2 diabetes in individuals of Mexican ancestry (PMID: 24915262). These individuals do not respond to treatment with sulfonylureas, unlike individuals with HNF1A-MODY (PMID: 29844095). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

- -

HNF1A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Type 2 diabetes mellitus

Other:1

not provided, no classification provided

literature only

SNPedia

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

.;D;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.1

N;.;.;N;N

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

D;.;.;D;D

Sift4G

Uncertain

0.029

D;T;D;D;T

Polyphen

0.99

.;.;.;.;D

Vest4

0.76

MutPred

0.74

Gain of methylation at E508 (P = 0.0019);.;.;Gain of methylation at E508 (P = 0.0019);Gain of methylation at E508 (P = 0.0019);

MVP

0.98

MPC

0.39

ClinPred

0.23

GERP RS

4.1

gMVP

0.66

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