17-80470947-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PS1_ModeratePM1PP5_Very_StrongBP4
The NM_002522.4(NPTX1):c.1165G>A(p.Gly389Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_002522.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPTX1 | ENST00000306773.5 | c.1165G>A | p.Gly389Arg | missense_variant | Exon 5 of 5 | 1 | NM_002522.4 | ENSP00000307549.4 | ||
NPTX1 | ENST00000571100.2 | c.451G>A | p.Gly151Arg | missense_variant | Exon 4 of 4 | 4 | ENSP00000511957.1 | |||
NPTX1 | ENST00000535681.1 | n.1767G>A | non_coding_transcript_exon_variant | Exon 3 of 4 | 2 | |||||
NPTX1 | ENST00000695485.1 | n.588G>A | non_coding_transcript_exon_variant | Exon 4 of 4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251148Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135786
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461550Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727038
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74280
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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Segregates with disease in many affected individuals with features consistent with NPTX1- related spinocerebellar ataxia from several families in published literature (PMID: 34788392, 35288776); Published functional studies suggest a damaging effect on endoplasmic reticulum morphology and increased cytotoxicity (PMID: 34788392); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35288776, 34788392) -
NPTX1: PP1:Strong, PS4, PM2:Supporting, PP2, PS3:Supporting -
Spinocerebellar ataxia 50 Pathogenic:2
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 34788392). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001184956 /PMID: 34788392). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 34788392). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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Inborn genetic diseases Pathogenic:1
The c.1165G>A (p.G389R) alteration is located in exon 5 (coding exon 5) of the NPTX1 gene. This alteration results from a G to A substitution at nucleotide position 1165, causing the glycine (G) at amino acid position 389 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251148) total alleles studied. The highest observed frequency was 0.001% (1/113534) of European (non-Finnish) alleles. This alteration has been reported to segregate with disease in multiple families with features consistent with NPTX1-related cerebellar ataxia (Coutelier, 2022; Helmchen, 2022). This amino acid position is well conserved in available vertebrate species. Functional analysis demonstrated that the p.G389R variant increased aggregated endoplasmic reticulum morphology, triggered hyperplasia of the endoplasmic reticulum, induced ATF6-mediated endoplasmic reticulum stress, and increased cytotoxicity (Coutelier, 2022). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at