rs121918237

chr9-137233234-G-Achr9-137233234-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: SLC34A3 NM_001177316.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001177316.2
• 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 [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	UniProt
SLC34A3	NM_001177316.2	c.586G>A	p.Gly196Arg	missense_variant	7/13	ENST00000673835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC34A3	ENST00000673835.1	c.586G>A	p.Gly196Arg	missense_variant	7/13		NM_001177316.2	P1
SLC34A3	ENST00000361134.2	c.586G>A	p.Gly196Arg	missense_variant	7/13	2		P1
SLC34A3	ENST00000538474.5	c.586G>A	p.Gly196Arg	missense_variant	7/13	5		P1
SLC34A3	ENST00000673865.1	c.586G>A	p.Gly196Arg	missense_variant	7/10

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151924 Hom.: 0 Cov.: 32

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

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

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

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

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive hypophosphatemic bone disease Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Nov 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute	Mar 08, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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: 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

Other links and lift over

dbSNP: rs121918237; hg19: chr9-140127686;