chr9-137233223-C-T

Position:

chr9-137233223-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001177316.2(SLC34A3):c.575C>T(p.Ser192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,574,476 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 0 hom. )

Consequence

SLC34A3
NM_001177316.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.53

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]

SLC34A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-137233223-C-T is Pathogenic according to our data. Variant chr9-137233223-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137233223-C-T is described in Lovd as [Likely_pathogenic]. Variant chr9-137233223-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC34A3	NM_001177316.2 linkuse as main transcript	c.575C>T	p.Ser192Leu	missense_variant	7/13	ENST00000673835.1	NP_001170787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SLC34A3	ENST00000673835.1 linkuse as main transcript	c.575C>T	p.Ser192Leu	missense_variant	7/13		NM_001177316.2	ENSP00000501114	P1
SLC34A3	ENST00000361134.2 linkuse as main transcript	c.575C>T	p.Ser192Leu	missense_variant	7/13	2		ENSP00000355353	P1
SLC34A3	ENST00000538474.5 linkuse as main transcript	c.575C>T	p.Ser192Leu	missense_variant	7/13	5		ENSP00000442397	P1
SLC34A3	ENST00000673865.1 linkuse as main transcript	c.575C>T	p.Ser192Leu	missense_variant	7/10			ENSP00000501101

Frequencies

GnomAD3 genomes

AF:

0.000553

AC:

AN:

151870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000436

AC:

AN:

183402

Hom.:

AF XY:

0.000419

AC XY:

AN XY:

100328

show subpopulations

Gnomad AFR exome

AF:

0.000104

Gnomad AMR exome

AF:

0.0000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000962

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000741

AC:

1054

AN:

1422606

Hom.:

Cov.:

AF XY:

0.000737

AC XY:

519

AN XY:

704614

show subpopulations

Gnomad4 AFR exome

AF:

0.000154

Gnomad4 AMR exome

AF:

0.0000251

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.0000614

Gnomad4 NFE exome

AF:

0.000935

Gnomad4 OTH exome

AF:

0.000375

GnomAD4 genome

AF:

0.000553

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00110

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000686

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.000241

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000335

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2024	Likely a European founder mutation that has been associated with a less severe HHRH phenotype in the homozygous state and increased risk for renal calcifications in the heterozygous state (PMID: 32150856); Published functional studies demonstrate that although this variant does not have a significant impact on membrane sorting of phosphate, it severely reduces transport activity (PMID: 30798342, 36596813); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 34805638, 32155322, 34666334, 30586318, 31672324, 16358215, 18996815, 19820004, 30798342, 16358214, 34743040, 35689455, 37432176, 36596813, 37414395, 24700880, 32150856) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 192 of the SLC34A3 protein (p.Ser192Leu). This variant is present in population databases (rs199690076, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (HHRH) (PMID: 16358214, 18996815, 19820004). 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: 198610). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC34A3: PM3:Very Strong, PM2, PS3:Supporting -
Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Autosomal recessive hypophosphatemic bone disease

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Nov 05, 2020	The c.575C>T variant in the SLC34A3 gene is a homozygous missense variant, which results in the substitution of the a serine residue at the 192 position to leucine (p.Ser192Leu). This variant localizes to coding exon 7 of the SLC34A3 gene (13 exons total; NM_080877. In- silico analyses are inconsistent regarding predictions of the effect of this variant on protein structure and/or function (PROVEAN: neutral SIFT: damaging; PolyPhen-2: benign). This variant has been observed in the Genome Aggregation Database (gnomAD) at a low frequency (allele frequency = 0.0004615, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported to segregate with disease in multiple individuals with HHRH either in the homozygous state or with another SLC34A3 variant (PMIDs: 19820004, 18996815, 16358215, 16358214, 30798342). A different missense change at the same amino acid residue (S192W) has been described to be disease causing. -

SLC34A3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The SLC34A3 c.575C>T variant is predicted to result in the amino acid substitution p.Ser192Leu. This variant was reported in patients with hereditary hypophosphatemic rickets with hypercalciuria (Bergwitz et al. 2006. PubMed ID: 16358214; Lorenz-Depiereux et al. 2006. PubMed ID: 16358215; Page et al. 2008. PubMed ID: 18996815; Tencza et al. 2009. PubMed ID: 19820004; Schönauer et al. 2019. PubMed ID: 30798342; Table S1, Hureaux et al. 2019. PubMed ID: 31672324). Of note, some individuals heterozygous for this particular variant present with milder hypercalciuria and some signs of renal calcification (Tencza et al. 2009. PubMed ID: 19820004; Schönauer et al. 2019. PubMed ID: 30798342). This variant is reported in 0.096% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Benign

-0.080

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.67

P;P

Vest4

0.91

MVP

0.83

MPC

0.046

ClinPred

0.094

GERP RS

2.7

Varity_R

0.36

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over