NM_006262.4:c.421G>T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_006262.4(PRPH):c.421G>T(p.Asp141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00542 in 1,545,564 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006262.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRPH | ENST00000257860.9 | c.421G>T | p.Asp141Tyr | missense_variant | Exon 1 of 9 | 1 | NM_006262.4 | ENSP00000257860.4 | ||
PRPH | ENST00000451891.4 | c.100-18G>T | intron_variant | Intron 1 of 5 | 5 | ENSP00000408897.4 | ||||
TROAP-AS1 | ENST00000553259.1 | n.2451C>A | non_coding_transcript_exon_variant | Exon 6 of 8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00360 AC: 548AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00321 AC: 451AN: 140550Hom.: 0 AF XY: 0.00292 AC XY: 223AN XY: 76292
GnomAD4 exome AF: 0.00562 AC: 7830AN: 1393228Hom.: 0 Cov.: 31 AF XY: 0.00531 AC XY: 3651AN XY: 687128
GnomAD4 genome AF: 0.00360 AC: 549AN: 152336Hom.: 0 Cov.: 33 AF XY: 0.00337 AC XY: 251AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1Other:1
- -
- -
- -
not specified Uncertain:2
Variant summary: PRPH c.421G>T (p.Asp141Tyr) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of 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 0.0032 in 140550 control chromosomes. This frequency does not allow conclusions about variant significance due to lack of accurate figures supporting the prevalence of PRPH-associated Amyotrophic Lateral Sclerosis Type 1 and limited reported association of this gene with the phenotype (Clingen, 2022). Furthermore, low to variable penetrance, role as a susceptibility factor and possibility of pre-symptomatic individuals in the control populations have each been speculated (Gromicho_2020). c.421G>T has been reported in the literature in individuals affected with features of Familial Amyotrophic Lateral Sclerosis (FALS) and in unaffected controls (example, Gromicho_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Amyotrophic Lateral Sclerosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32638105). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; LB, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
The D141Y variant in the PRPH gene has been reported previously in the homozygous and heterozygous state in unrelated individuals with ALS (Leung et al., 2004; Corrado et al., 2011). The D141Y variant is observed in 373/64280 (0.58%) alleles in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The D141Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D141Y as a variant of uncertain significance. -
PRPH-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Amyotrophic lateral sclerosis, susceptibility to Other:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at