rs1024639436
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PP3_ModeratePP5_StrongBS2
The ENST00000617811.5(HNF1B):c.1085C>T(p.Ser362Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,858 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: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
HNF1B
ENST00000617811.5 missense
ENST00000617811.5 missense
Scores
9
5
1
Clinical Significance
Conservation
PhyloP100: 7.75
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.874
PP5
Variant 17-37710624-G-A is Pathogenic according to our data. Variant chr17-37710624-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 594889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1B | NM_000458.4 | c.1085C>T | p.Ser362Phe | missense_variant | 5/9 | ENST00000617811.5 | NP_000449.1 | |
LOC124903989 | XR_007065732.1 | n.5957G>A | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1B | ENST00000617811.5 | c.1085C>T | p.Ser362Phe | missense_variant | 5/9 | 1 | NM_000458.4 | ENSP00000480291 | ||
HNF1B | ENST00000621123.4 | c.1007C>T | p.Ser336Phe | missense_variant | 5/9 | 1 | ENSP00000482711 | P1 | ||
HNF1B | ENST00000613727.4 | c.1007C>T | p.Ser336Phe | missense_variant | 5/7 | 1 | ENSP00000477524 | |||
HNF1B | ENST00000614313.4 | c.1085C>T | p.Ser362Phe | missense_variant | 5/8 | 5 | ENSP00000482529 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461858Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 727230
GnomAD4 exome
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29
AN:
1461858
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33
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12
AN XY:
727230
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 21, 2023 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 362 of the HNF1B protein (p.Ser362Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diabetes (PMID: 27913849). ClinVar contains an entry for this variant (Variation ID: 594889). 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 not expected to disrupt HNF1B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 07, 2017 | - - |
Maturity onset diabetes mellitus in young Pathogenic:1
Likely risk allele, flagged submission | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | HNF1B gene mutations are associated with early onset diabetes and pancreatic atrophy. It is also associated with multiple renal manifestations including renal cysts, Tubulointerstitial disease, glomerulocystic disease, renal hypoplasia, hypomagnesemia. However no sufficient evidence is found to ascertain the role of this particular variant rs1024639436, yet. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Loss of phosphorylation at S362 (P = 0.0433);.;Loss of phosphorylation at S362 (P = 0.0433);.;Loss of phosphorylation at S362 (P = 0.0433);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at