chr12-120994351-G-A

Position:

chr12-120994351-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000257555.11(HNF1A):c.901G>A(p.Ala301Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,600,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HNF1A
ENST00000257555.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.92

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23773482).

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HNF1A	NM_000545.8 linkuse as main transcript	c.901G>A	p.Ala301Thr	missense_variant	4/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.901G>A	p.Ala301Thr	missense_variant	4/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.901G>A	p.Ala301Thr	missense_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.901G>A	p.Ala301Thr	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.901G>A	p.Ala301Thr	missense_variant	4/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000451

AC:

AN:

221838

Hom.:

AF XY:

0.0000417

AC XY:

AN XY:

119982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000322

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.0000596

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000530

Gnomad NFE exome

AF:

0.0000506

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1447908

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

719076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000713

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.0000145

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000488

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 301 of the HNF1A protein (p.Ala301Thr). This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 10027593, 19336507). 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. 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. ClinVar contains an entry for this variant (Variation ID: 586796). -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Madras Diabetes Research Foundation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.43

.;T;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Uncertain

-0.0046

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.23

N;.;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.50

T;.;T;T

Sift4G

Benign

0.77

T;T;T;T

Polyphen

0.037

.;.;.;B

Vest4

0.25

MutPred

0.53

Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);Gain of glycosylation at A301 (P = 7e-04);

MVP

0.96

MPC

0.12

ClinPred

0.034

GERP RS

3.8

gMVP

0.72

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