17-37710601-C-T
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_000458.4(HNF1B):c.1108G>A(p.Gly370Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000458.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1B | ENST00000617811.5 | c.1108G>A | p.Gly370Ser | missense_variant | Exon 5 of 9 | 1 | NM_000458.4 | ENSP00000480291.1 | ||
HNF1B | ENST00000621123.4 | c.1030G>A | p.Gly344Ser | missense_variant | Exon 5 of 9 | 1 | ENSP00000482711.1 | |||
HNF1B | ENST00000613727.4 | c.1030G>A | p.Gly344Ser | missense_variant | Exon 5 of 7 | 1 | ENSP00000477524.1 | |||
HNF1B | ENST00000614313.4 | c.1108G>A | p.Gly370Ser | missense_variant | Exon 5 of 8 | 5 | ENSP00000482529.1 |
Frequencies
GnomAD3 genomes AF: 0.000427 AC: 65AN: 152152Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251104Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135712
GnomAD4 exome AF: 0.000111 AC: 162AN: 1461806Hom.: 2 Cov.: 33 AF XY: 0.0000880 AC XY: 64AN XY: 727214
GnomAD4 genome AF: 0.000447 AC: 68AN: 152270Hom.: 1 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Observed in patients with MODY or renal cysts and diabetes syndrome; however, additional information is not available (Bellanne-Chantelot et al., 2005; Poitou et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22432796, 28453780, 21163139, 25700310, 27535533, 16249435, 24097065, 32041611) -
- -
- -
BS1, BS2 -
Renal cysts and diabetes syndrome Uncertain:1
- -
HNF1B-related disorder Uncertain:1
The HNF1B c.1108G>A variant is predicted to result in the amino acid substitution p.Gly370Ser. This variant has been reported in individuals with maturity-onset diabetes of the young type 5, also referred to as renal cysts and diabetes syndrome (Bellanne-Chantelot et al. 2005. PubMed ID: 16249435; referred to as rs113042313, Elashi et al. 2022. PubMed ID: 36613572). It has also been reported an individual without diabetes (Supplementary Tables 2 and 3, Flannick et al. 2013. PubMed ID: 24097065). No family or functional studies were performed to help assess its pathogenicity. This variant is reported in 0.18% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome Uncertain:1
The heterozygous c.1108G>A (p.Gly370Ser) missense variant identified in HNF1B has been previously reported in association with maturity-onset diabetes of the young type 5/ renal cysts and diabetes syndrome [PMID: 16249435;PMID: 2243279;PMID: 24097065]. Functional studies to evaluate the potential pathogenicity of this variant were not performed. This variant has been reported as a variant of uncertain in the ClinVar database [Variation ID:379811]. The variant has 0.001521 allele frequency in the African/African-American subpopulation of the gnomAD(v3) database (63 out of 41,432 heterozygous alleles, 1 homozygous allele). The affected Gly370 residue is not highly conserved and in silico tools provide conflicting interpretations about potential pathogenicity of this variant. Based on the available evidence, the c.1108G>A (p.Gly370Ser) missense variant in the HNF1B gene is reported as a variant of uncertain significance. -
Maturity onset diabetes mellitus in young Uncertain:1
The p.G370S variant (also known as c.1108G>A), located in coding exon 5 of the HNF1B gene, results from a G to A substitution at nucleotide position 1108. The glycine at codon 370 is replaced by serine, an amino acid with similar properties. This variant was detected in a cohort of individuals with maturity-onset diabetes of young(MODY)/renal cysts and diabetes (RCAD) (Bellanné-Chantelot C et al. Diabetes, 2005 Nov;54:3126-32; Poitou C et al. Transpl. Int., 2012 May;25:564-72). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
not specified Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at