rs121918675

chr17-37739490-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000458.4(HNF1B):c.494G>A(p.Arg165His) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.57

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.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000458.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-37739491-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 635684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-37739490-C-T is Pathogenic according to our data. Variant chr17-37739490-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-37739490-C-T is described in UniProt as null. Variant chr17-37739490-C-T is described in UniProt as null. Variant chr17-37739490-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-37739490-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.494G>A	p.Arg165His	missense_variant	2/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.494G>A	p.Arg165His	missense_variant	2/9	1	NM_000458.4
HNF1B	ENST00000621123.4	c.494G>A	p.Arg165His	missense_variant	2/9	1		P1
HNF1B	ENST00000613727.4	c.494G>A	p.Arg165His	missense_variant	2/7	1
HNF1B	ENST00000614313.4	c.494G>A	p.Arg165His	missense_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cysts and diabetes syndrome Pathogenic:4

Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Jan 17, 2019	- -
Likely pathogenic, criteria provided, single submitter	literature only	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jul 06, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 16, 2020	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduces the transactivation capacity of the protein (PMID: 15509593). Computational tools predict that this variant is damaging. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 12, 2021	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1B protein function. ClinVar contains an entry for this variant (Variation ID: 12647). This missense change has been observed in individual(s) with renal cysts and diabetes syndrome (PMID: 15068978, 22051731, 24254850, 31198537). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 165 of the HNF1B protein (p.Arg165His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Aug 04, 2021

- -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Madras Diabetes Research Foundation

-

- -

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

Nov 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.98
MutPred		0.97		Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);
MVP		0.99
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.60
gMVP		0.86

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: rs121918675; hg19: chr17-36099481;