chr12-120994321-C-T

Position:

chr12-120994321-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS1BP2BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.871C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 291 (p.(Pro291Ser)) of NM_000545.8. •This variant has been observed in unknown phase with the variant c.494G>A, p.Trp165Ter (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). Functional studies demonstrated the p.Pro291Ser protein has abnormal nuclear localization above 75% of wildtype, indicating that this variant does not impact protein function (PMID:32910913) (BS3_Supporting). Lastly, this variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00001163, which is greater than or equal to the MDEP threshold for BS1 (≥0.000033) (BS1). In summary, c.871C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): BP2, BS3_Supporting, BS1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831856/MONDO:0007453/017

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.661

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 Likely_benign. Variant got -6 ACMG points.

BP2

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

BS1

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

BS3

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.871C>T	p.Pro291Ser	missense_variant	4/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 linkuse as main transcript	c.871C>T	p.Pro291Ser	missense_variant	4/10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 linkuse as main transcript	c.871C>T	p.Pro291Ser	missense_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.871C>T	p.Pro291Ser	missense_variant	4/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.871C>T	p.Pro291Ser	missense_variant	4/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000254

AC:

AN:

239706

Hom.:

AF XY:

0.000276

AC XY:

AN XY:

130220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

Gnomad ASJ exome

AF:

0.00559

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.000341

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1457718

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

724894

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00487

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.000465

GnomAD4 genome

AF:

0.000145

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Pro291Ser variant in HNF1A is classified as benign because it has been identified in 0.5% (54/9958) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org) and several species (including at least 4 mammals, namely the bat, bushbaby, squirel, mole) carry a Serine (Ser) at this position despite high nearby amino acid conservation. Computational prediction tools further suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BS1, BP4_Strong. -

Monogenic diabetes

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jan 03, 2022

The c.871C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 291 (p.(Pro291Ser)) of NM_000545.8. • This variant has been observed in unknown phase with the variant c.494G>A, p.Trp165Ter (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). Functional studies demonstrated the p.Pro291Ser protein has abnormal nuclear localization above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). Lastly, this variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00001163, which is greater than or equal to the MDEP threshold for BS1 (≥0.000033) (BS1). In summary, c.871C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved ***): BP2, BS3_Supporting, BS1 -

Maturity onset diabetes mellitus in young

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2023

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 20, 2023

- -

Maturity-onset diabetes of the young type 3

Benign:1

Likely benign, 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. 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. -

HNF1A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.060

CADD

Benign

5.2

DANN

Benign

0.47

DEOGEN2

Benign

0.38

.;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.74

T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Uncertain

-0.27

PrimateAI

Benign

0.46

PROVEAN

Benign

0.20

N;.;N;N

REVEL

Uncertain

0.57

Sift

Benign

0.42

T;.;T;T

Sift4G

Benign

0.61

T;T;T;T

Polyphen

0.0

.;.;.;B

Vest4

0.40

MVP

0.96

MPC

0.12

ClinPred

0.016

GERP RS

1.6

gMVP

0.46

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