17-37744827-C-T

Position:

• chr17-37744827-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000458.4(HNF1B):​c.58G>A​(p.Gly20Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,397,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.37

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.58G>A	p.Gly20Arg	missense_variant	1/9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.58G>A	p.Gly20Arg	missense_variant	1/9	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.58G>A	p.Gly20Arg	missense_variant	1/9	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.58G>A	p.Gly20Arg	missense_variant	1/7	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.58G>A	p.Gly20Arg	missense_variant	1/8	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397482 Hom.: 0 Cov.: 35 AF XY: 0.00000144 AC XY: 1 AN XY: 694730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 25, 2023

Variant summary: HNF1B c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, N-terminal (IPR006899) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.58G>A has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young (Sampathkumar_2022). This report does not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 5 (Renal Cysts And Diabetes Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34741762). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;M;.;.;.;.
PrimateAI	Pathogenic	0.82	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.86
MutPred		0.84		Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);
MVP		0.91
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.60
gMVP		0.83

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: rs1052557621; hg19: chr17-36104818;