rs886043813

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000458.4(HNF1B):c.884G>C(p.Arg295Pro) 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. 11/19 in silico tools predict a damaging 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. R295H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

HNF1B
NM_000458.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.57

Publications

1 publications found

Variant links:

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]

HNF1B Gene-Disease associations (from GenCC):

renal cysts and diabetes syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
permanent neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
transient neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
medullary sponge kidney
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal dysplasia, bilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal dysplasia, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal hypomagnesemia 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
unilateral multicystic dysplastic kidney
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNF1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 9 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 chr17-37731756-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288154.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 72 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: 2.0703 (below the threshold of 3.09). GenCC associations: The gene is linked to unilateral multicystic dysplastic kidney, renal dysplasia, unilateral, renal cysts and diabetes syndrome, medullary sponge kidney, renal hypomagnesemia 2, renal dysplasia, bilateral, diabetes mellitus, noninsulin-dependent, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 17-37731756-C-G is Pathogenic according to our data. Variant chr17-37731756-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 635630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4 link	c.884G>C	p.Arg295Pro	missense_variant	Exon 4 of 9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5 link	c.884G>C	p.Arg295Pro	missense_variant	Exon 4 of 9	1	NM_000458.4	ENSP00000480291.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal cysts and diabetes syndrome

Pathogenic:3

May 29, 2019

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:1

Mar 21, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15509593, 30754209, 25700310, 33532864, 17924661, 15068978, 15930087) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;T;T;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.1

M;.;.;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.92

Sift4G

Uncertain

0.0020

D;D;D;T;D

Polyphen

0.99

D;.;.;.;.

Vest4

0.99

MutPred

0.88

Loss of MoRF binding (P = 3e-04);.;Loss of MoRF binding (P = 3e-04);.;Loss of MoRF binding (P = 3e-04);

MVP

0.98

ClinPred

0.99

GERP RS

5.6

Varity_R

0.94

gMVP

0.98

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over