rs121918672

chr17-37731814-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000458.4(HNF1B):c.826C>T(p.Arg276Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.08

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-37731814-G-A is Pathogenic according to our data. Variant chr17-37731814-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-37731814-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.826C>T	p.Arg276Ter	stop_gained	4/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.826C>T	p.Arg276Ter	stop_gained	4/9	1	NM_000458.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cysts and diabetes syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -
Pathogenic, criteria provided, single submitter	literature only	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jul 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.R276* in HNF1B (NM_000458.4) has been reported previously in affected patients (Furuta H et al; Fujimoto K et al).Functional studies reveal a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.R276* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Nov 12, 2018	A heterozygous nonsense variant, NM_000458.3(HNF1B):c.826C>T, has been identified in exon 4 of 9 of the HNF1B gene. The variant is predicted to result in a premature stop codon at position 276 of the protein (NP_000449.1(HNF1B):p.(Arg276*)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, 1000G). The variant has been previously described as pathogenic and segregated with disease in at least one family with renal cysts and diabetes syndrome (MODY5) (ClinVar; Furuta, H. et al., 2002; Fujimoto, K. et al., 2007; Verhave, J.C., 2016). Functional analysis showed that the mutant allele produces inactive protein (Furuta, H. et al., 2002). In addition, p.(Arg276*) caused significant decrease in glucose-stimulated insulin secretion in MIN6 cells (Fujimoto, K. et al., 2007). Several truncating variants up and downstream predicted to result in NMD have been reported pathogenic (ClinVar, HGMD, Decipher). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 21, 2023	This premature translational stop signal has been observed in individual(s) with cystic kidney (PMID: 31131422). ClinVar contains an entry for this variant (Variation ID: 12640). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg276*) in the HNF1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1B are known to be pathogenic (PMID: 9398836, 12148114, 15068978, 20378641). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2022	This variant is expected to result in the loss of a functional protein. This variant has been identified in at least one individual with MODY or renal cysts. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -

Autosomal dominant medullary cystic kidney disease with or without hyperuricemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Mar 01, 2018

- -

Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.96
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs121918672; hg19: chr17-36091805;