rs121918674

chr17-37739541-G-C

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.443C>G(p.Ser148Trp) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S148L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr17-37739541-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 635698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-37739541-G-C is Pathogenic according to our data. Variant chr17-37739541-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-37739541-G-C is described in UniProt as null. Variant chr17-37739541-G-C is described in UniProt as null. Variant chr17-37739541-G-C is described in Lovd as [Likely_pathogenic]. Variant chr17-37739541-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.443C>G	p.Ser148Trp	missense_variant	2/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.443C>G	p.Ser148Trp	missense_variant	2/9	1	NM_000458.4
HNF1B	ENST00000621123.4	c.443C>G	p.Ser148Trp	missense_variant	2/9	1		P1
HNF1B	ENST00000613727.4	c.443C>G	p.Ser148Trp	missense_variant	2/7	1
HNF1B	ENST00000614313.4	c.443C>G	p.Ser148Trp	missense_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cysts and diabetes syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -
Pathogenic, criteria provided, single submitter	literature only	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jul 06, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2019

Identified in two siblings in the published literature, with one sibling having neonatal diabetes mellitus and a few renal cyts and the other siblng having neonatal polycystic dysplastic kidneys and a transient episode of hyperglycemia, whose clinically unaffected mother had low level mosaicisam for the variant (Yorifuji et al., 2004); Published functional studies demonstrate a damaging effect with impaired function of HNF1B by loss of function and dominant negative mechanisms (Yorifuji et al., 2004); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15181075) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;D;D;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.87	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.92
MutPred		0.96		Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);
MVP		0.99
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.84
gMVP		0.99

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: rs121918674; hg19: chr17-36099532;