chr9-137234125-G-A

Variant names:

• chr9-137234125-G-A
• rs34664302
• NM_001177316.2:c.942G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001177316.2(SLC34A3):​c.942G>A​(p.Ala314Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,588,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A314A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SLC34A3 NM_001177316.2 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.52
• Publications: 3 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: SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.942G>A	p.Ala314Ala	synonymous	Exon 10 of 13	NP_001170787.2
	SLC34A3	NM_001177317.2		c.942G>A	p.Ala314Ala	synonymous	Exon 10 of 13	NP_001170788.2
	SLC34A3	NM_080877.3		c.942G>A	p.Ala314Ala	synonymous	Exon 10 of 13	NP_543153.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A3	ENST00000673835.1	MANE Select	c.942G>A	p.Ala314Ala	synonymous	Exon 10 of 13	ENSP00000501114.1
	SLC34A3	ENST00000361134.2	TSL:2	c.942G>A	p.Ala314Ala	synonymous	Exon 10 of 13	ENSP00000355353.2
	SLC34A3	ENST00000538474.5	TSL:5	c.942G>A	p.Ala314Ala	synonymous	Exon 10 of 13	ENSP00000442397.1

Frequencies

GnomAD3 genomes AF: 0.0000333 AC: 5 AN: 150068 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000320 AC: 7 AN: 218422 AF XY: 0.0000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000590

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000503

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000215 AC: 31 AN: 1438626 Hom.: 0 Cov.: 35 AF XY: 0.0000210 AC XY: 15 AN XY: 715092

African (AFR) AF: 0.0000300 AC: 1 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 43746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39924

Middle Eastern (MID) AF: 0.000203 AC: 1 AN: 4924

European-Non Finnish (NFE) AF: 0.0000226 AC: 25 AN: 1107334

Other (OTH) AF: 0.0000335 AC: 2 AN: 59742

GnomAD4 genome AF: 0.0000333 AC: 5 AN: 150068 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 73128

African (AFR) AF: 0.0000247 AC: 1 AN: 40504

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000591 AC: 4 AN: 67662

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.0000367 Hom.: 2

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive hypophosphatemic bone disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	21
DANN	Benign	0.59
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34664302; hg19: chr9-140128577;