17-37731634-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP6BS1BS2

The NM_000458.4(HNF1B):c.1006C>G(p.His336Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,613,732 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H336R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

HNF1B
NM_000458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 7.78

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a region_of_interest Disordered (size 28) in uniprot entity HNF1B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000458.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-37731633-T-C is described in Lovd as [Likely_pathogenic].

BP6

Variant 17-37731634-G-C is Benign according to our data. Variant chr17-37731634-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 595653.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000223 (34/152284) while in subpopulation NFE AF= 0.000485 (33/68028). AF 95% confidence interval is 0.000355. There are 1 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4 link	c.1006C>G	p.His336Asp	missense_variant	Exon 4 of 9	ENST00000617811.5	NP_000449.1	P35680-1Q6FHW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5 link	c.1006C>G	p.His336Asp	missense_variant	Exon 4 of 9	1	NM_000458.4	ENSP00000480291.1		P35680-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152166

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000184

AC:

AN:

250172

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000181

AC:

265

AN:

1461448

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

149

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000223

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74470

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000320

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 31, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal cysts and diabetes syndrome

Uncertain:1Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jul 06, 2019

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Jan 09, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H336D variant (also known as c.1006C>G), located in coding exon 4 of the HNF1B gene, results from a C to G substitution at nucleotide position 1006. The histidine at codon 336 is replaced by aspartic acid, an amino acid with similar properties. This alteration was first described in two unrelated patients with renal hypodysplasia (RHD) associated with chronic renal insufficiency; the father and brother of one were each heterozygous for the alteration but had normal renal evaluations, including ultrasound and biochemical measurements (Weber S et al. J. Am. Soc. Nephrol., 2006 Oct;17:2864-70). In a MODY family, which included a proband with renal and urogenital anomalies, this alteration was identified in three of four individual's with a history of diabetes; however, an HNF1A alteration at a canonical splice site was present in all four diabetic family members (Karges B et al. Diabetes Care, 2007 Jun;30:1613-4). This alteration has been reported in an additional four individuals with congenital anomalies of the kidney and urinary tract (CAKUT); however, given the presence of this alteration in population databases, the authors were not convinced that p.H336D was causative (Hwang DY et al. Kidney Int., 2014 Jun;85:1429-33; Nicolaou N et al. Kidney Int., 2016 Feb;89:476-86). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.;T;T;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.077

MetaRNN

Uncertain

0.57

D;D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

2.0

M;.;.;.;.

PrimateAI

Uncertain

0.52

Sift4G

Benign

0.57

T;T;T;T;T

Polyphen

0.42

B;.;.;.;.

Vest4

0.74

MVP

0.93

ClinPred

0.24

GERP RS

5.2

Varity_R

0.37

gMVP

0.66

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