rs121918237

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_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

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]

SLC34A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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, 5 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 [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 rank	MANE	Protein	UniProt
SLC34A3	NM_001177316.2 link	c.586G>A	p.Gly196Arg	missense_variant	Exon 7 of 13	ENST00000673835.1	NP_001170787.2	Q8N130

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC34A3	ENST00000673835.1 link	c.586G>A	p.Gly196Arg	missense_variant	Exon 7 of 13		NM_001177316.2	ENSP00000501114.1	Q8N130
SLC34A3	ENST00000361134.2 link	c.586G>A	p.Gly196Arg	missense_variant	Exon 7 of 13	2		ENSP00000355353.2	Q8N130
SLC34A3	ENST00000538474.5 link	c.586G>A	p.Gly196Arg	missense_variant	Exon 7 of 13	5		ENSP00000442397.1	Q8N130
SLC34A3	ENST00000673865.1 link	c.586G>A	p.Gly196Arg	missense_variant	Exon 7 of 10			ENSP00000501101.1	A0A669KB63

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151924

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000645

AC:

AN:

185974

AF XY:

0.0000886

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 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.:

Cov.:

AF XY:

0.0000780

AC XY:

AN XY:

704890

show subpopulations

African (AFR)

AF:

0.0000308

AC:

AN:

32422

American (AMR)

AF:

0.000126

AC:

AN:

39830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.0000539

AC:

AN:

37092

South Asian (SAS)

AF:

0.0000365

AC:

AN:

82118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.0000851

AC:

AN:

1092800

Other (OTH)

AF:

0.000102

AC:

AN:

58712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151924

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41360

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000593

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000424

AC:

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

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 08, 2024

Molecular Genetics Laboratory, Biobizkaia Health Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 29, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PS3, PM2_P, PP1, PP5; Variant was found in homozygous state -

Nov 28, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Mar 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC34A3 function (PMID: 22159077). For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.0064

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;D

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.30

LIST_S2

Pathogenic

0.98

D;.

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

-0.076

MutationAssessor

Benign

1.9

L;L

PhyloP100

0.77

PrimateAI

Benign

0.47

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

GERP RS

-1.3

Varity_R

0.70

gMVP

0.71

Mutation Taster

=21/79

disease causing (ClinVar)

(source)

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

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rs121918237

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over