rs201304511
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003052.5(SLC34A1):c.644+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000077 in 1,610,972 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_003052.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC34A1 | NM_003052.5 | c.644+1G>A | splice_donor_variant, intron_variant | ENST00000324417.6 | NP_003043.3 | |||
SLC34A1 | NM_001167579.2 | c.644+1G>A | splice_donor_variant, intron_variant | NP_001161051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC34A1 | ENST00000324417.6 | c.644+1G>A | splice_donor_variant, intron_variant | 1 | NM_003052.5 | ENSP00000321424.4 | ||||
SLC34A1 | ENST00000512593.5 | c.644+1G>A | splice_donor_variant, intron_variant | 2 | ENSP00000423022.1 | |||||
SLC34A1 | ENST00000507685.5 | n.729G>A | non_coding_transcript_exon_variant | 6/10 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151916Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000777 AC: 19AN: 244652Hom.: 0 AF XY: 0.0000674 AC XY: 9AN XY: 133572
GnomAD4 exome AF: 0.0000809 AC: 118AN: 1459056Hom.: 0 Cov.: 44 AF XY: 0.0000827 AC XY: 60AN XY: 725802
GnomAD4 genome AF: 0.0000395 AC: 6AN: 151916Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74196
ClinVar
Submissions by phenotype
Nephrocalcinosis;C0392525:Nephrolithiasis Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Sep 08, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 09, 2023 | This sequence change affects a donor splice site in intron 6 of the SLC34A1 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 SLC34A1 are known to be pathogenic (PMID: 26047794). This variant is present in population databases (rs201304511, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with clinical features of infantile hypercalcemia (PMID: 26047794, 28893421, 29959532). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 234926). 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. - |
SLC34A1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 04, 2024 | The SLC34A1 c.644+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous and compound heterozygous states in individuals with infantile hypercalcemia (Schlingmann et al. 2016. PubMed ID: 26047794; Daga et al. 2017. PubMed ID: 28893421; Hureaux et al. 2018. PubMed ID: 29959532). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt consensus splice donor sites in SLC34A1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Hypercalcemia, infantile, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 06, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at