8-42856296-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_030954.4(RNF170):āc.640A>Gā(p.Ile214Val) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,586,676 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_030954.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000231 AC: 52AN: 225378Hom.: 2 AF XY: 0.000368 AC XY: 45AN XY: 122268
GnomAD4 exome AF: 0.000130 AC: 187AN: 1434410Hom.: 5 Cov.: 32 AF XY: 0.000184 AC XY: 131AN XY: 712576
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74450
ClinVar
Submissions by phenotype
Autosomal dominant sensory ataxia 1 Pathogenic:2
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not specified Uncertain:2
Variant summary: RNF170 c.640A>G (p.Ile214Val) results in a conservative amino acid change located in the domain of unknown function DUF1232 (IPR010652) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 225378 control chromosomes, including 2 homozygotes, occurring predominantly at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database, suggesting this variant may be benign. c.640A>G has been reported in the literature in the heterozygous state in an individual affected with spastic paraparesis who underwent WES, however no second variant was identified (Sahin_2022). This report does not provide unequivocal conclusions about association of the variant with autosomal recessive spastic paraplegia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at