rs756863825
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate
The NM_003060.4(SLC22A5):c.40T>A(p.Trp14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,916 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W14C) has been classified as Uncertain significance.
Frequency
Consequence
NM_003060.4 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 |
---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.40T>A | p.Trp14Arg | missense_variant | 1/10 | ENST00000245407.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.40T>A | p.Trp14Arg | missense_variant | 1/10 | 1 | NM_003060.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460916Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726830
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp14 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC22A5 protein function. ClinVar contains an entry for this variant (Variation ID: 580421). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 32371215). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 14 of the SLC22A5 protein (p.Trp14Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. - |
Decreased circulating carnitine concentration Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 28, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at