2-44275695-TC-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000341.4(SLC3A1):c.163delC(p.Gln55ArgfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000341.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC3A1 | NM_000341.4 | c.163delC | p.Gln55ArgfsTer51 | frameshift_variant | Exon 1 of 10 | ENST00000260649.11 | NP_000332.2 | |
SLC3A1 | XM_011533047.4 | c.163delC | p.Gln55ArgfsTer51 | frameshift_variant | Exon 1 of 10 | XP_011531349.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC3A1 | ENST00000260649.11 | c.163delC | p.Gln55ArgfsTer51 | frameshift_variant | Exon 1 of 10 | 1 | NM_000341.4 | ENSP00000260649.6 | ||
ENSG00000285542 | ENST00000649044.1 | n.*174delC | non_coding_transcript_exon_variant | Exon 6 of 15 | ENSP00000497083.1 | |||||
ENSG00000285542 | ENST00000649044.1 | n.*174delC | 3_prime_UTR_variant | Exon 6 of 15 | ENSP00000497083.1 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251132Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135772
GnomAD4 exome AF: 0.000238 AC: 348AN: 1461820Hom.: 0 Cov.: 34 AF XY: 0.000248 AC XY: 180AN XY: 727216
GnomAD4 genome AF: 0.000118 AC: 18AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74366
ClinVar
Submissions by phenotype
Cystinuria Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gln55Argfs*51) in the SLC3A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC3A1 are known to be pathogenic (PMID: 24610330, 25109415, 25964309). This variant is present in population databases (rs779932118, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with cystinuria (PMID: 11260385, 25964309). This variant is also known as c.161delC. ClinVar contains an entry for this variant (Variation ID: 502014). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
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The SLC3A1 p.Q55Rfs*51 variant was identified in 13 of 634 proband chromosomes (frequency: 0.021) from individuals or families with cystinuria; the variant has been reported in cystinuria patients in the heterozygous, compound heterozygous and homozygous state (Bisceglia_2001_PMID:11260385; Gitomer_1998_PMID:9768685; Font-Llitjós_2005_PMID:15635077; Tostivint_2017_PMID:28646536; Brauers_2006_PMID:18947684). The variant was identified in dbSNP (ID: rs779932118) and ClinVar (classified as pathogenic by EGL Genetic Diagnostics). The variant was identified in control databases in 17 of 282536 chromosomes at a frequency of 0.00006017 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 16 of 128970 chromosomes (freq: 0.000124) and Latino in 1 of 35410 chromosomes (freq: 0.000028), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.161del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 55 and leads to a premature stop codon 51 amino acids downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the SLC3A1 gene are an established mechanism of disease in cystinuria and is the type of variant expected to cause the disorder. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at