9-137233633-T-G

Variant names:

• chr9-137233633-T-G
• rs28407527
• NM_001177316.2:c.757T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001177316.2(SLC34A3):​c.757T>G​(p.Leu253Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L253L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC34A3 NM_001177316.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001204
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A3	NM_001177316.2	MANE Select	c.757T>G	p.Leu253Val	missense splice_region	Exon 8 of 13	NP_001170787.2
	SLC34A3	NM_001177317.2		c.757T>G	p.Leu253Val	missense splice_region	Exon 8 of 13	NP_001170788.2
	SLC34A3	NM_080877.3		c.757T>G	p.Leu253Val	missense splice_region	Exon 8 of 13	NP_543153.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A3	ENST00000673835.1	MANE Select	c.757T>G	p.Leu253Val	missense splice_region	Exon 8 of 13	ENSP00000501114.1
	SLC34A3	ENST00000361134.2	TSL:2	c.757T>G	p.Leu253Val	missense splice_region	Exon 8 of 13	ENSP00000355353.2
	SLC34A3	ENST00000538474.5	TSL:5	c.757T>G	p.Leu253Val	missense splice_region	Exon 8 of 13	ENSP00000442397.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460336 Hom.: 0 Cov.: 44 AF XY: 0.00000138 AC XY: 1 AN XY: 726508

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111720

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.81
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.8
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.18
Sift	Benign	0.082	T
Sift4G	Benign	0.076	T
Polyphen		0.69	P
Vest4		0.46
MutPred		0.48		Gain of sheet (P = 0.0477)
MVP		0.34
MPC		0.17
ClinPred		0.67	D
GERP RS		2.3
Varity_R		0.096
gMVP		0.47
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.040
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: rs28407527; hg19: chr9-140128085;