5-177386473-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_003052.5(SLC34A1):c.439G>A(p.Val147Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,092 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
SLC34A1
NM_003052.5 missense
NM_003052.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 6.78
Genes affected
SLC34A1 (HGNC:11019): (solute carrier family 34 member 1) Enables sodium:phosphate symporter activity. Involved in several processes, including phosphate ion homeostasis; phosphate ion transport; and response to lead ion. Located in several cellular components, including apical plasma membrane; mitotic spindle; and nuclear speck. Implicated in several diseases, including Fanconi syndrome (multiple); chronic kidney disease; hereditary hypophosphatemic rickets with hypercalciuria; hypophosphatemic nephrolithiasis/osteoporosis 1; and nephrolithiasis. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a transmembrane_region Helical; Name=M2 (size 17) in uniprot entity NPT2A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003052.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC34A1 | NM_003052.5 | c.439G>A | p.Val147Met | missense_variant | 5/13 | ENST00000324417.6 | NP_003043.3 | |
SLC34A1 | NM_001167579.2 | c.439G>A | p.Val147Met | missense_variant | 5/9 | NP_001161051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC34A1 | ENST00000324417.6 | c.439G>A | p.Val147Met | missense_variant | 5/13 | 1 | NM_003052.5 | ENSP00000321424 | P1 | |
SLC34A1 | ENST00000512593.5 | c.439G>A | p.Val147Met | missense_variant | 5/9 | 2 | ENSP00000423022 | |||
SLC34A1 | ENST00000507685.5 | n.523G>A | non_coding_transcript_exon_variant | 5/10 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251438Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135910
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461862Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727238
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypophosphatemic nephrolithiasis/osteoporosis 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 26, 2002 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 12, 2022 | Experimental studies have shown that this missense change affects SLC34A1 function (PMID: 12324554, 14672348). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12932). This missense change has been observed in individual(s) with demineralization and hypophosphatemia (PMID: 12324554). This variant is present in population databases (rs121918611, gnomAD 0.002%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 147 of the SLC34A1 protein (p.Val147Met). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.97
.;D
Vest4
MutPred
Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP
MPC
0.34
ClinPred
D
GERP RS
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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