14-67729199-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_152443.3(RDH12):c.667G>T(p.Val223Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_152443.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RDH12 | NM_152443.3 | c.667G>T | p.Val223Phe | missense_variant | Exon 8 of 9 | ENST00000551171.6 | NP_689656.2 | |
RDH12 | XM_047430965.1 | c.667G>T | p.Val223Phe | missense_variant | Exon 8 of 9 | XP_047286921.1 | ||
ZFYVE26 | XM_047431173.1 | c.*543C>A | 3_prime_UTR_variant | Exon 42 of 42 | XP_047287129.1 | |||
GPHN | XM_047430879.1 | c.1313-5996G>T | intron_variant | Intron 14 of 14 | XP_047286835.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RDH12 | ENST00000551171.6 | c.667G>T | p.Val223Phe | missense_variant | Exon 8 of 9 | 1 | NM_152443.3 | ENSP00000449079.1 | ||
RDH12 | ENST00000267502.3 | c.667G>T | p.Val223Phe | missense_variant | Exon 7 of 8 | 5 | ENSP00000267502.3 | |||
RDH12 | ENST00000552873.1 | n.36G>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 5 | |||||
ZFYVE26 | ENST00000394455.6 | n.3288+12C>A | intron_variant | Intron 14 of 14 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460526Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726650
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Leber congenital amaurosis Pathogenic:1
Variant summary: RDH12 c.667G>T (p.Val223Phe) 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 was absent in 248940 control chromosomes. c.667G>T has been reported in the literature in homozygous individuals affected with Retinitis pigmentosa (Colombo_2021) and Cone-rod dystrophy (Liu_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33576794, 33090715). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Retinal dystrophy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at