NM_031407.7:c.13070G>A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5
The NM_031407.7(HUWE1):c.13070G>A(p.Arg4357His) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,015 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_031407.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HUWE1 | NM_031407.7 | c.13070G>A | p.Arg4357His | missense_variant | Exon 84 of 84 | ENST00000262854.11 | NP_113584.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome AF: 9.13e-7 AC: 1AN: 1095015Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 360461
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
HUWE1-related neurodevelopmental disorder Pathogenic:1
A heterozygous missense variant, NM_031407.5(HUWE1):c.13070G>A, has been identified in exon 84 of 84 of the HUWE1 gene. The variant is predicted to result in a minor amino acid change from arginine to histidine at position 4357 of the protein (NP_113584.3(HUWE1):p.(Arg4357His)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the HECT functional domain. In-silico predictions for this variant are consistently pathogenic (Polyphen, CADD, Mutation Taster). The variant is absent in population databases (gnomAD). This variant has not been previously reported in clinical cases. Subsequent analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -
Inborn genetic diseases Uncertain:1
The c.13070G>A (p.R4357H) alteration is located in exon 84 (coding exon 81) of the HUWE1 gene. This alteration results from a G to A substitution at nucleotide position 13070, causing the arginine (R) at amino acid position 4357 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at