17-37731634-G-C

Position:

• chr17-37731634-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM5 BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 7.78

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 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, Uncertain_significance=5, Benign=1}.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.1006C>G	p.His336Asp	missense_variant	4/9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.1006C>G	p.His336Asp	missense_variant	4/9	1	NM_000458.4	ENSP00000480291.1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152166 Hom.: 1 Cov.: 32

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: 46 AN: 250172 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 135318

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.: 2 Cov.: 32 AF XY: 0.000205 AC XY: 149 AN XY: 727000

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: 34 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74470

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.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2018	- -
Likely benign, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -

Renal cysts and diabetes syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	literature only	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jul 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2017

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	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
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	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	2.0	M;.;.;.;.
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.42	B;.;.;.;.
Vest4		0.74
MVP		0.93
ClinPred		0.24	T
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

Other links and lift over

dbSNP: rs138986885; hg19: chr17-36091625;