rs886043813

chr17-37731756-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000458.4(HNF1B):c.884G>A(p.Arg295His) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• 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 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr17-37731757-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 635631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 17-37731756-C-T is Pathogenic according to our data. Variant chr17-37731756-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288154.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=3}. Variant chr17-37731756-C-T is described in UniProt as null. Variant chr17-37731756-C-T is described in UniProt as null. Variant chr17-37731756-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.884G>A	p.Arg295His	missense_variant	4/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.884G>A	p.Arg295His	missense_variant	4/9	1	NM_000458.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2018	Not found in the total gnomAD dataset, and the data is high quality (0/276870 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16249435, 17924661, 34487217, 27838256, 15068978, 31131422, 31595705, Weckwerth2021[paper], 33574344, 34440516, 15509593) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 25, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg295 amino acid residue in HNF1B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16249435, 23979948, 31825128). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 295 of the HNF1B protein (p.Arg295His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with HNF1B-related disorders and/or renal cysts and diabetes syndrome (PMID: 15068978, 16249435, 31131422, 33574344). ClinVar contains an entry for this variant (Variation ID: 288154). 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. Experimental studies have shown that this missense change affects HNF1B function (PMID: 15509593). -

Renal cysts and diabetes syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	Jan 04, 2022	- -
Pathogenic, criteria provided, single submitter	literature only	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jul 06, 2019	- -

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

Jun 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;T;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MutPred		0.86		Loss of MoRF binding (P = 0.0051);.;Loss of MoRF binding (P = 0.0051);.;Loss of MoRF binding (P = 0.0051);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs886043813; hg19: chr17-36091747;