12-120979061-C-T

Position:

chr12-120979061-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000257555.11(HNF1A):c.293C>T(p.Ala98Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,611,476 control chromosomes in the GnomAD database, including 921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A98T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.022 ( 52 hom., cov: 32)

Exomes 𝑓: 0.030 ( 869 hom. )

Consequence

HNF1A
ENST00000257555.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 7.35

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000257555.11

BP4

Computational evidence support a benign effect (MetaRNN=0.0042442083).

BP6

Variant 12-120979061-C-T is Benign according to our data. Variant chr12-120979061-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120979061-C-T is described in Lovd as [Benign]. Variant chr12-120979061-C-T is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HNF1A	NM_000545.8 linkuse as main transcript	c.293C>T	p.Ala98Val	missense_variant	1/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.293C>T	p.Ala98Val	missense_variant	1/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.293C>T	p.Ala98Val	missense_variant	1/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.293C>T	p.Ala98Val	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.293C>T	p.Ala98Val	missense_variant	1/10	1	NM_000545.8	ENSP00000257555	P4
HNF1A-AS1	ENST00000619441.1 linkuse as main transcript	n.128+1583G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3342

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00543

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0656

Gnomad FIN

AF:

0.0475

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0278

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0290

AC:

6974

AN:

240478

Hom.:

164

AF XY:

0.0322

AC XY:

4227

AN XY:

131112

show subpopulations

Gnomad AFR exome

AF:

0.00543

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.0000551

Gnomad SAS exome

AF:

0.0660

Gnomad FIN exome

AF:

0.0416

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0300

AC:

43743

AN:

1459166

Hom.:

869

Cov.:

AF XY:

0.0313

AC XY:

22689

AN XY:

725618

show subpopulations

Gnomad4 AFR exome

AF:

0.00487

Gnomad4 AMR exome

AF:

0.0121

Gnomad4 ASJ exome

AF:

0.0348

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0670

Gnomad4 FIN exome

AF:

0.0427

Gnomad4 NFE exome

AF:

0.0290

Gnomad4 OTH exome

AF:

0.0275

GnomAD4 genome

AF:

0.0219

AC:

3337

AN:

152310

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1725

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00544

Gnomad4 AMR

AF:

0.0134

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0650

Gnomad4 FIN

AF:

0.0475

Gnomad4 NFE

AF:

0.0278

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0280

Hom.:

Bravo

AF:

0.0181

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0257

AC:

220

ExAC

AF:

0.0288

AC:

3492

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2014	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Maturity onset diabetes mellitus in young

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 18, 2018	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. -
Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in this gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. Good response to sulfonylureas. However, rs1800574 localized in the DNA-binding domain of the HNF1A gene (p.Ala98Val) doesn't directly predispose to early-onset Diabetes Mellitus even if the prevalence of the variant is high. -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Nonpapillary renal cell carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 01, 2019

ACMG criteria: BA1 (overall MAF in gnomAD 3%, 6.6% in South Asian in gnomAD, ~3% in other subpop), BS2 (346 cases and 404 controls in T2DM ) [Revel score 0.597, PP3 (6), BP4 (4)= conflicting evidence, not using] [not using BP6]: benign -

Maturity-onset diabetes of the young type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

.;D;T;D;T;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

MetaRNN

Benign

0.0042

T;T;T;T;T;T

MetaSVM

Uncertain

0.40

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

N;.;.;.;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.063

T;.;.;.;T;T

Sift4G

Benign

0.090

T;T;T;T;T;T

Polyphen

0.21

.;.;.;.;.;B

Vest4

0.46

MPC

0.27

ClinPred

0.086

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

gMVP

0.90

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