rs55834942

chr12-120999311-G-Achr12-120999311-G-Cchr12-120999311-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_000545.8(HNF1A):c.1545G>A(p.Thr515=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,798 control chromosomes in the GnomAD database, including 26,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.13 ( 1790 hom., cov: 32)

Exomes 𝑓: 0.17 ( 24387 hom. )

Consequence

HNF1A
NM_000545.8 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -1.47

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015262663).

BP6

Variant 12-120999311-G-A is Benign according to our data. Variant chr12-120999311-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129232.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1}. Variant chr12-120999311-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.47 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNF1A	NM_000545.8 linkuse as main transcript	c.1545G>A	p.Thr515=	synonymous_variant	8/10	ENST00000257555.11
HNF1A	NM_001306179.2 linkuse as main transcript	c.1545G>A	p.Thr515=	synonymous_variant	8/10
HNF1A	NM_001406915.1 linkuse as main transcript	c.1353G>A	p.Thr451=	synonymous_variant	7/9
HNF1A	XM_024449168.2 linkuse as main transcript	c.1545G>A	p.Thr515=	synonymous_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1545G>A	p.Thr515=	synonymous_variant	8/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20000

AN:

151990

Hom.:

1789

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0321

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0378

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.152

GnomAD3 exomes

AF:

0.140

AC:

35137

AN:

251142

Hom.:

3256

AF XY:

0.141

AC XY:

19190

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.0887

Gnomad ASJ exome

AF:

0.222

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0396

Gnomad FIN exome

AF:

0.223

Gnomad NFE exome

AF:

0.196

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.174

AC:

253901

AN:

1461690

Hom.:

24387

Cov.:

AF XY:

0.171

AC XY:

124242

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0288

Gnomad4 AMR exome

AF:

0.0922

Gnomad4 ASJ exome

AF:

0.218

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0430

Gnomad4 FIN exome

AF:

0.227

Gnomad4 NFE exome

AF:

0.194

Gnomad4 OTH exome

AF:

0.167

GnomAD4 genome

AF:

0.131

AC:

19992

AN:

152108

Hom.:

1790

Cov.:

AF XY:

0.128

AC XY:

9510

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0320

Gnomad4 AMR

AF:

0.116

Gnomad4 ASJ

AF:

0.216

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0380

Gnomad4 FIN

AF:

0.222

Gnomad4 NFE

AF:

0.193

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.175

Hom.:

3928

Bravo

AF:

0.122

TwinsUK

AF:

0.191

AC:

707

ALSPAC

AF:

0.200

AC:

772

ESP6500AA

AF:

0.0397

AC:

175

ESP6500EA

AF:

0.192

AC:

1654

ExAC

AF:

0.140

AC:

16968

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.203

EpiControl

AF:

0.203

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2013	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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Insulin-resistant diabetes mellitus

Uncertain:1

Uncertain significance, 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 and response to sulfonylureas. However, there is insufficient evidence that rs55834942 plays a role in MODY and or micro and macro vascular complications of Diabetes Mellitus and needs further clinical evaluation. -

Nonpapillary renal cell carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

This alteration is classified as 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

Invitae

Feb 01, 2024

- -

Maturity-onset diabetes of the young type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

Cadd

Benign

6.5

Dann

Benign

0.88

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0015

MutationTaster

Benign

1.7e-7

P;P;P;P

Sift4G

Benign

0.33

Vest4

0.26

GERP RS

-7.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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