rs121918675

Variant names:

• chr17-37739490-C-G
• NM_000458.4:c.494G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-37739490-C-G
• chr17-37739490-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000458.4(HNF1B):​c.494G>C​(p.Arg165Pro) 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 Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 12 ACMG points.

• PM1: In a helix (size 19) in uniprot entity HNF1B_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-37739490-C-G is Pathogenic according to our data. Variant chr17-37739490-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 635683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-37739490-C-G is described in Lovd as [Pathogenic]. Variant chr17-37739490-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.494G>C	p.Arg165Pro	missense_variant	Exon 2 of 9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.494G>C	p.Arg165Pro	missense_variant	Exon 2 of 9	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.494G>C	p.Arg165Pro	missense_variant	Exon 2 of 9	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.494G>C	p.Arg165Pro	missense_variant	Exon 2 of 7	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.494G>C	p.Arg165Pro	missense_variant	Exon 2 of 8	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal cysts and diabetes syndrome Pathogenic:1

Jul 06, 2019

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

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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	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.99
MutPred		0.90		Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);
MVP		0.99
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-36099481;