rs121909257
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The ENST00000298854.7(RAPSN):c.566C>T(p.Ala189Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,878 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A189G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000298854.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAPSN | NM_005055.5 | c.566C>T | p.Ala189Val | missense_variant | 3/8 | ENST00000298854.7 | NP_005046.2 | |
LOC124902673 | XR_007062669.1 | n.145-4547G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAPSN | ENST00000298854.7 | c.566C>T | p.Ala189Val | missense_variant | 3/8 | 1 | NM_005055.5 | ENSP00000298854 | P1 | |
RAPSN | ENST00000352508.7 | c.566C>T | p.Ala189Val | missense_variant | 3/6 | 1 | ENSP00000298853 | |||
RAPSN | ENST00000529341.1 | c.566C>T | p.Ala189Val | missense_variant | 3/5 | 1 | ENSP00000431732 | |||
RAPSN | ENST00000524487.5 | c.532-859C>T | intron_variant | 5 | ENSP00000435551 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251458Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461878Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727238
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Fetal akinesia deformation sequence 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2008 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 04, 2024 | Variant summary: RAPSN c.566C>T (p.Ala189Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251458 control chromosomes (gnomAD). c.566C>T has been reported in the literature in the compound heterozygous state in two siblings born at term affected with Fetal Akinesia Deformation Sequence (FADS), from a family where the variant segregated with disease and there was a history of preterm abortion (Michalk_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18252226). ClinVar contains an entry for this variant (Variation ID: 8059). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at