rs121918235

Variant names:

• chr9-137234634-C-A
• rs121918235
• NM_001177316.2:c.1238C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-137234634-C-A
• chr9-137234634-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001177316.2(SLC34A3):​c.1238C>A​(p.Ala413Glu) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A413V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC34A3 NM_001177316.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.79
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• hereditary hypophosphatemic rickets with hypercalciuria

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001177316.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 9-137234634-C-A is Pathogenic according to our data. Variant chr9-137234634-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177316.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A3	NM_001177316.2	MANE Select	c.1238C>A	p.Ala413Glu	missense	Exon 12 of 13	NP_001170787.2	Q8N130
	SLC34A3	NM_001177317.2		c.1238C>A	p.Ala413Glu	missense	Exon 12 of 13	NP_001170788.2	Q8N130
	SLC34A3	NM_080877.3		c.1238C>A	p.Ala413Glu	missense	Exon 12 of 13	NP_543153.2	Q8N130

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A3	ENST00000673835.1	MANE Select	c.1238C>A	p.Ala413Glu	missense	Exon 12 of 13	ENSP00000501114.1	Q8N130
	SLC34A3	ENST00000361134.2	TSL:2	c.1238C>A	p.Ala413Glu	missense	Exon 12 of 13	ENSP00000355353.2	Q8N130
	SLC34A3	ENST00000538474.5	TSL:5	c.1238C>A	p.Ala413Glu	missense	Exon 12 of 13	ENSP00000442397.1	Q8N130

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal recessive hypophosphatemic bone disease (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		3.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.93		Gain of solvent accessibility (P = 0.0411)
MVP		0.85
MPC		0.30
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.93
gMVP		0.91
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918235; hg19: chr9-140129086;