chr9-137231707-C-T

Variant names:

• chr9-137231707-C-T
• rs566626846
• NM_001177316.2:c.5C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001177316.2(SLC34A3):​c.5C>T​(p.Pro2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,612,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: SLC34A3 NM_001177316.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.751
• 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: AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030525446).

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.5C>T	p.Pro2Leu	missense	Exon 2 of 13	NP_001170787.2	Q8N130
	SLC34A3	NM_001177317.2		c.5C>T	p.Pro2Leu	missense	Exon 2 of 13	NP_001170788.2	Q8N130
	SLC34A3	NM_080877.3		c.5C>T	p.Pro2Leu	missense	Exon 2 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.5C>T	p.Pro2Leu	missense	Exon 2 of 13	ENSP00000501114.1	Q8N130
	SLC34A3	ENST00000361134.2	TSL:2	c.5C>T	p.Pro2Leu	missense	Exon 2 of 13	ENSP00000355353.2	Q8N130
	SLC34A3	ENST00000538474.5	TSL:5	c.5C>T	p.Pro2Leu	missense	Exon 2 of 13	ENSP00000442397.1	Q8N130

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251010 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1460748 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 726678

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111904

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74412

African (AFR) AF: 0.0000241 AC: 1 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.75
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.013	B
Vest4		0.24
MutPred		0.27		Loss of catalytic residue at P2 (P = 0.0056)
MVP		0.41
MPC		0.29
ClinPred		0.22	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.56
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs566626846; hg19: chr9-140126159;