rs121918237
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001177316.2(SLC34A3):c.586G>A(p.Gly196Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,574,890 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000077 ( 0 hom. )
Consequence
SLC34A3
NM_001177316.2 missense
NM_001177316.2 missense
Scores
4
7
8
Clinical Significance
Conservation
PhyloP100: 0.766
Genes affected
SLC34A3 (HGNC:20305): (solute carrier family 34 member 3) This gene encodes a member of SLC34A transporter family of proteins, and is expressed primarily in the kidney. It is involved in transporting phosphate into cells via sodium cotransport in the renal brush border membrane, and contributes to the maintenance of inorganic phosphate concentration in the kidney. Mutations in this gene are associated with hereditary hypophosphatemic rickets with hypercalciuria. Alternatively spliced transcript variants varying in the 5' UTR have been found for this gene.[provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 9-137233234-G-A is Pathogenic according to our data. Variant chr9-137233234-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC34A3 | NM_001177316.2 | c.586G>A | p.Gly196Arg | missense_variant | 7/13 | ENST00000673835.1 | NP_001170787.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC34A3 | ENST00000673835.1 | c.586G>A | p.Gly196Arg | missense_variant | 7/13 | NM_001177316.2 | ENSP00000501114 | P1 | ||
SLC34A3 | ENST00000361134.2 | c.586G>A | p.Gly196Arg | missense_variant | 7/13 | 2 | ENSP00000355353 | P1 | ||
SLC34A3 | ENST00000538474.5 | c.586G>A | p.Gly196Arg | missense_variant | 7/13 | 5 | ENSP00000442397 | P1 | ||
SLC34A3 | ENST00000673865.1 | c.586G>A | p.Gly196Arg | missense_variant | 7/10 | ENSP00000501101 |
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 151924Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000645 AC: 12AN: 185974Hom.: 0 AF XY: 0.0000886 AC XY: 9AN XY: 101528
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GnomAD4 exome AF: 0.0000773 AC: 110AN: 1422966Hom.: 0 Cov.: 36 AF XY: 0.0000780 AC XY: 55AN XY: 704890
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GnomAD4 genome AF: 0.0000658 AC: 10AN: 151924Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74216
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive hypophosphatemic bone disease Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute | Mar 08, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | Nov 28, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Aug 29, 2024 | ACMG Criteria: PS3, PM2_P, PP1, PP5; Variant was found in homozygous state - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 15, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 196 of the SLC34A3 protein (p.Gly196Arg). This variant is present in population databases (rs121918237, gnomAD 0.02%). This missense change has been observed in individual(s) with hypophosphatemic rickets (PMID: 16358214, 18523928, 26789268). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1431). 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 not expected to disrupt SLC34A3 protein function. Experimental studies have shown that this missense change affects SLC34A3 function (PMID: 22159077). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Pathogenic
D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
A;A
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MutPred
Gain of MoRF binding (P = 0.0529);Gain of MoRF binding (P = 0.0529);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at