NM_030954.4:c.595C>T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_030954.4(RNF170):c.595C>T(p.Arg199Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,439,842 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 Pathogenic (★★).
Frequency
Consequence
NM_030954.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000439 AC: 1AN: 227970Hom.: 0 AF XY: 0.00000809 AC XY: 1AN XY: 123644
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1439842Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1AN XY: 715804
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant sensory ataxia 1 Pathogenic:2
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive spastic paraplegia 85 (MIM#619686). The mechanism of autosomal dominant sensory ataxia 1 (MIM#608984) is unclear, but toxic gain of function has been suggested (PMID: 21115467, PMID: 31636353). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (16 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least four unrelated families with sensory ataxia, with or without vestibular areflexia or pyramidal involvement (PMID: 21115467, PMID: 32943585, PMID: 34469621). (SP) 0901 - This variant has strong evidence for segregation with disease (PMID: 21115467, PMID: 32943585, PMID: 34469621). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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Spastic paraplegia 85, autosomal recessive Pathogenic:1
Variant summary: RNF170 c.595C>T (p.Arg199Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 227970 control chromosomes (gnomAD). c.595C>T has been reported in the literature in multiple individuals affected with Autosomal dominant sensory ataxia and the variant segregated with the disease (example: Valdamins_2011 and Cortese_2020). These data indicate that the variant is very likely to be associated with disease. One submitter (OMIM) have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at