rs121918237

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

Scores

4
7
8

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.766
Variant links:
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]

Genome browser will be placed here

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
SLC34A3NM_001177316.2 linkuse as main transcriptc.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
SLC34A3ENST00000673835.1 linkuse as main transcriptc.586G>A p.Gly196Arg missense_variant 7/13 NM_001177316.2 ENSP00000501114 P1
SLC34A3ENST00000361134.2 linkuse as main transcriptc.586G>A p.Gly196Arg missense_variant 7/132 ENSP00000355353 P1
SLC34A3ENST00000538474.5 linkuse as main transcriptc.586G>A p.Gly196Arg missense_variant 7/135 ENSP00000442397 P1
SLC34A3ENST00000673865.1 linkuse as main transcriptc.586G>A p.Gly196Arg missense_variant 7/10 ENSP00000501101

Frequencies

GnomAD3 genomes
AF:
0.0000658
AC:
10
AN:
151924
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000645
AC:
12
AN:
185974
Hom.:
0
AF XY:
0.0000886
AC XY:
9
AN XY:
101528
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000146
Gnomad SAS exome
AF:
0.0000390
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000519
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000773
AC:
110
AN:
1422966
Hom.:
0
Cov.:
36
AF XY:
0.0000780
AC XY:
55
AN XY:
704890
show subpopulations
Gnomad4 AFR exome
AF:
0.0000308
Gnomad4 AMR exome
AF:
0.000126
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000539
Gnomad4 SAS exome
AF:
0.0000365
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000851
Gnomad4 OTH exome
AF:
0.000102
GnomAD4 genome
AF:
0.0000658
AC:
10
AN:
151924
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74216
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000832
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000424
AC:
5

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 providedclinical testingMolecular Genetics Laboratory, Biocruces Bizkaia Health Research InstituteMar 08, 2024- -
Pathogenic, criteria provided, single submitterclinical testingIntergen, Intergen Genetics and Rare Diseases Diagnosis CenterNov 28, 2023- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2006- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin BerlinSep 22, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Immunology and Genetics KaiserslauternAug 29, 2024ACMG Criteria: PS3, PM2_P, PP1, PP5; Variant was found in homozygous state -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 15, 2023This 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Benign
-0.0064
T
BayesDel_noAF
Uncertain
0.020
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.74
D;D
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.79
FATHMM_MKL
Benign
0.30
N
LIST_S2
Pathogenic
0.98
D;.
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
-0.076
T
MutationAssessor
Benign
1.9
L;L
MutationTaster
Benign
0.016
A;A
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.0
N;N
REVEL
Uncertain
0.64
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
0.93
P;P
Vest4
0.79
MutPred
0.92
Gain of MoRF binding (P = 0.0529);Gain of MoRF binding (P = 0.0529);
MVP
0.78
MPC
0.095
ClinPred
0.090
T
GERP RS
-1.3
Varity_R
0.70
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918237; hg19: chr9-140127686; API