2-44312754-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_000341.4(SLC3A1):c.1500+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000287 in 1,604,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000341.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC3A1 | NM_000341.4 | c.1500+1G>T | splice_donor_variant, intron_variant | Intron 8 of 9 | ENST00000260649.11 | NP_000332.2 | ||
SLC3A1 | XM_011533047.4 | c.1500+1G>T | splice_donor_variant, intron_variant | Intron 8 of 9 | XP_011531349.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC3A1 | ENST00000260649.11 | c.1500+1G>T | splice_donor_variant, intron_variant | Intron 8 of 9 | 1 | NM_000341.4 | ENSP00000260649.6 | |||
ENSG00000285542 | ENST00000649044.1 | n.*1511+1G>T | splice_donor_variant, intron_variant | Intron 13 of 14 | ENSP00000497083.1 |
Frequencies
GnomAD3 genomes AF: 0.0000270 AC: 4AN: 148158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249462Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134910
GnomAD4 exome AF: 0.0000288 AC: 42AN: 1456836Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 24AN XY: 724978
GnomAD4 genome AF: 0.0000270 AC: 4AN: 148158Hom.: 0 Cov.: 32 AF XY: 0.0000276 AC XY: 2AN XY: 72456
ClinVar
Submissions by phenotype
Cystinuria Pathogenic:3
This sequence change affects a donor splice site in intron 8 of the SLC3A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC3A1 are known to be pathogenic (PMID: 24610330, 25109415, 25964309). This variant is present in population databases (no rsID available, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with cystinuria (PMID: 8731106, 28646536). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284275). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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PVS1, PM2, PM3_Strong -
not provided Pathogenic:2
DNA sequence analysis of the SLC3A1 gene demonstrated a sequence change in the canonical splice donor site of intron 8, c.1500+1G>T. This sequence change has been described in the gnomAD database with a frequency of 0.0044% in the non-Finnish European subpopulation (dbSNP rs886042834). This sequence change has previously been described in multiple individuals with SLC3A1-related cystinuria in the homozygous and compound heterozygous states (PMID: 28049243, 28646536, 28717662, 11748844, 8731106, 11260385). This sequence change is predicted to affect normal splicing of the SLC3A1 gene and result in an abnormal protein, however functional studies have not been performed to prove this conclusively. Based on these collective evidences, this sequence change is classified as pathogenic. -
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Inborn genetic diseases Pathogenic:1
The c.1500+1G>T intronic alteration consists of a G to T substitution one nucleotide after coding exon 8 of the SLC3A1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (6/249462) total alleles studied. The highest observed frequency was 0.004% (5/112884) of European (non-Finnish) alleles. This alteration was detected in the homozygous state, and in conjunction with another alteration in SLC3A1, in multiple individuals with SLC3A1-related cystinuria and co-segregates with disease in several families (Harnevik, 2001; Tostivint, 2017; Gaildrat, 2017; Horsford, 1996). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at