rs150841256
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong
The NM_001177316.2(SLC34A3):c.448+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,606,892 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001177316.2 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC34A3 | NM_001177316.2 | c.448+1G>A | splice_donor_variant | ENST00000673835.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC34A3 | ENST00000673835.1 | c.448+1G>A | splice_donor_variant | NM_001177316.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152102Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000157 AC: 37AN: 235288Hom.: 1 AF XY: 0.000180 AC XY: 23AN XY: 127954
GnomAD4 exome AF: 0.000398 AC: 579AN: 1454790Hom.: 1 Cov.: 43 AF XY: 0.000366 AC XY: 265AN XY: 723334
GnomAD4 genome AF: 0.000158 AC: 24AN: 152102Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 12AN XY: 74294
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 25, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 19, 2017 | The c.448+1G>A variant in the SLC34A3 gene has been reported previously, using alternate nomenclature g.1226G>A, in an individual with HHRH who was compound heterozygous for c.448+1G>A and another SLC34A3 variant (Phulwani et al., 2011). RT-PCR studies of c.448+1G>A indicate that it creates an alternative splice donor site upstream of the natural splice donor site in intron 5, leading to a frameshift and a truncated transcript (Phulwani et al., 2011). The c.448+1G>A variant is observed in 35/118640 (0.03%) alleles from individuals of non-Finnish European background and in 39/261838 (0.015%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret c.448+1G>A as a likely pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change affects a donor splice site in intron 5 of the SLC34A3 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 SLC34A3 are known to be pathogenic (PMID: 16358214, 16358215, 22159077). This variant is present in population databases (rs150841256, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. Disruption of this splice site has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (PMID: 21344632, 31440709). ClinVar contains an entry for this variant (Variation ID: 445687). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | SLC34A3: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting - |
Autosomal recessive hypophosphatemic bone disease Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 18, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at