rs199690076

Positions:

• chr9-137233223-C-G
• chr9-137233223-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001177316.2(SLC34A3):​c.575C>G​(p.Ser192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S192L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC34A3 NM_001177316.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.53

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137233223-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 9-137233223-C-G is Pathogenic according to our data. Variant chr9-137233223-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 444094.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC34A3	NM_001177316.2	c.575C>G	p.Ser192Trp	missense_variant	7/13	ENST00000673835.1	NP_001170787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC34A3	ENST00000673835.1	c.575C>G	p.Ser192Trp	missense_variant	7/13		NM_001177316.2	ENSP00000501114	P1
SLC34A3	ENST00000361134.2	c.575C>G	p.Ser192Trp	missense_variant	7/13	2		ENSP00000355353	P1
SLC34A3	ENST00000538474.5	c.575C>G	p.Ser192Trp	missense_variant	7/13	5		ENSP00000442397	P1
SLC34A3	ENST00000673865.1	c.575C>G	p.Ser192Trp	missense_variant	7/10			ENSP00000501101

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive hypophosphatemic bone disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.74
MutPred		0.88		Loss of disorder (P = 0.0066);Loss of disorder (P = 0.0066);
MVP		0.84
MPC		0.26
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.81
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199690076; hg19: chr9-140127675;