rs201777056
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_005050.4(ABCD4):āc.956A>Gā(p.Tyr319Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,384 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_005050.4 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCD4 | NM_005050.4 | c.956A>G | p.Tyr319Cys | missense_variant | 10/19 | ENST00000356924.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD4 | ENST00000356924.9 | c.956A>G | p.Tyr319Cys | missense_variant | 10/19 | 1 | NM_005050.4 | P1 | |
ENST00000554532.2 | n.1115+688A>G | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000797 AC: 12AN: 150534Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251364Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135872
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461850Hom.: 0 Cov.: 38 AF XY: 0.0000165 AC XY: 12AN XY: 727228
GnomAD4 genome ? AF: 0.0000797 AC: 12AN: 150534Hom.: 0 Cov.: 32 AF XY: 0.0000680 AC XY: 5AN XY: 73486
ClinVar
Submissions by phenotype
Methylmalonic acidemia with homocystinuria, type cblJ Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 26, 2021 | - - |
Cobalamin C disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2022 | Variant summary: ABCD4 c.956A>G (p.Tyr319Cys) 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 3.6e-05 in 251364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.956A>G has been reported in the literature in the compound heterozygous state in an individual who was affected with Methylmalonic Acidemia With Homocystinuria (Coelho_2012). In vitro experiments suggest that the variant does not impact protein localization, but that ATPase and cobalamin transport activities are lost compared to the wild-type ABCD4 protein (Kitai_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at