rs1800575

chr17-37739455-G-Achr17-37739455-G-T

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.529C>T(p.Arg177Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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:7
• Conservation: PhyloP100: 2.86

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 17-37739455-G-A is Pathogenic according to our data. Variant chr17-37739455-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-37739455-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.529C>T	p.Arg177Ter	stop_gained	2/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.529C>T	p.Arg177Ter	stop_gained	2/9	1	NM_000458.4
HNF1B	ENST00000621123.4	c.529C>T	p.Arg177Ter	stop_gained	2/9	1		P1
HNF1B	ENST00000613727.4	c.529C>T	p.Arg177Ter	stop_gained	2/7	1
HNF1B	ENST00000614313.4	c.529C>T	p.Arg177Ter	stop_gained	2/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cysts and diabetes syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1997	- -
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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 08, 2019	A heterozygous nonsense variant, NM_000458.4(HNF1B):c.529C>T, has been identified in exon 2 of 9 of the HNF1B gene. The variant is predicted to result in a premature stop codon at position 177 of the protein (NP_000449.1(HNF1B):p.(Arg177*)). This variant is predicted to result in loss of protein function through nonsense-mediated decay (Yabe, S. G. et al., 2015), which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in patients with maturity-onset diabetes of the young, MODY5 (ClinVar; Horikawa, Y. et al., 1997; Montoli, A. et al., 2002). It has also been shown to segregate with the disease in at least one family (Horikawa, Y. et al., 1997). Additionally, studies show impaired localisation and altered protein function (Horikawa, Y. et al., 1997; Tomura, H. et al., 1999; Gu, N. et al., 2006; Barbacci, E. et al., 2004). Several truncating variants have been reported pathogenic (ClinVar, Decipher). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 08, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12635). This premature translational stop signal has been observed in individual(s) with clinical features of renal cysts and diabetes syndrome (PMID: 9398836, 12148114). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg177*) 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	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2022	Published functional studies demonstrate a damaging effect due to a loss of transactivation activity, as well as a dominant negative effect and altered protein localization specific to certain cell types (Tomura et al., 1999); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9398836, 12148114, 31131422, 32939031, 10224045) -

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	0.53
Cadd	Pathogenic	49
Dann	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.97
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1800575; hg19: chr17-36099446;