17-37744641-C-T

Position:

chr17-37744641-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000458.4(HNF1B):c.244G>A(p.Asp82Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,612,540 control chromosomes in the GnomAD database, including 1 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 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 1 hom. )

Consequence

HNF1B
NM_000458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:7

Conservation

PhyloP100: 7.68

Variant links:

Genes affected

HNF1B (HGNC:11630): (HNF1 homeobox B) This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

HNF1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23211148).

BP6

Variant 17-37744641-C-T is Benign according to our data. Variant chr17-37744641-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193101.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=6}. Variant chr17-37744641-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000676 (103/152390) while in subpopulation AMR AF= 0.00111 (17/15310). AF 95% confidence interval is 0.000848. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1B	NM_000458.4 linkuse as main transcript	c.244G>A	p.Asp82Asn	missense_variant	1/9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5 linkuse as main transcript	c.244G>A	p.Asp82Asn	missense_variant	1/9	1	NM_000458.4	ENSP00000480291		P35680-1
HNF1B	ENST00000621123.4 linkuse as main transcript	c.244G>A	p.Asp82Asn	missense_variant	1/9	1		ENSP00000482711	P1	P35680-2
HNF1B	ENST00000613727.4 linkuse as main transcript	c.244G>A	p.Asp82Asn	missense_variant	1/7	1		ENSP00000477524
HNF1B	ENST00000614313.4 linkuse as main transcript	c.244G>A	p.Asp82Asn	missense_variant	1/8	5		ENSP00000482529

Frequencies

GnomAD3 genomes

AF:

0.000676

AC:

103

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000616

AC:

154

AN:

249854

Hom.:

AF XY:

0.000620

AC XY:

AN XY:

135432

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000964

AC:

1407

AN:

1460150

Hom.:

Cov.:

AF XY:

0.000965

AC XY:

701

AN XY:

726456

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000649

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000773

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152390

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000875

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000684

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2024	Reported in unrelated patients in published literature, including one individual with hyperuricemia, bilateral renal cysts and dysplasia, and stage 1 chronic kidney disease and an individual whose clinical information was not provided (PMID: 30666461, 31264968); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19639018, 26899772, 24897035, 27634015, 31264968, 34426522, 32041611, 30666461, 38025229, 30476936) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 21, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	HNF1B: BS1:Supporting, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 27, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified in HGMD as DM, related to HNF1B-related disease (reported in one patient, phenotype not specified). This variant is classified in ClinVar with 1 star as VUS by Emory. It is present in ExAC with a Max MAF of 0.12%. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	- -

Renal cysts and diabetes syndrome

Uncertain:1Benign: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. -
Uncertain significance, criteria provided, single submitter	literature only	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jul 06, 2019	- -

HNF1B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

The HNF1B c.244G>A variant is predicted to result in the amino acid substitution p.Asp82Asn. This variant has been reported in patients with features of HNF1B-related disorders; however, pathogenicity has not been established (Faguer et al. 2014. PubMed ID: 24897035; Brahm et al. 2016. PubMed ID: 27634015; Yu et al. 2019. PubMed ID: 31264968, supplementary table 6; Okorn et al. 2019. PubMed ID: 30666461; Kanda et al. 2016. PubMed ID: 26899772; Zuber et al. 2009. PubMed ID: 19639018). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is likely too common to be a primary cause of autosomal dominant disorders. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 11, 2019

ACMG criteria: PP3 (REVEL 0.890 + 7 predictors); PP4 (19639018, 26899772; variant also identified in patient in PMID: 24897035 (no clinical info, can't tell if overlap with other papers); BS2 (12 cases and 15 controls in T2Dgenes); BS1 (MAF in gnomAD EurNF population is 0.09%; 0.14% in ESP European pop)= scores as benign, but going to call as VUS given case reports and predictors (conflicting evidence). -

Autosomal dominant polycystic liver disease

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

Maturity onset diabetes mellitus in young

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;T;T;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.97

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.23

T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.79

Sift4G

Uncertain

0.015

D;D;D;D;D;D

Polyphen

0.58

P;.;.;.;.;.

Vest4

0.45

MVP

0.78

ClinPred

0.26

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.78

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