9-137233234-G-T

Variant names:

• chr9-137233234-G-T
• rs121918237
• NM_001177316.2:c.586G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001177316.2(SLC34A3):​c.586G>T​(p.Gly196Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000843 in 1,422,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G196R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: SLC34A3 NM_001177316.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.766
• Publications: 12 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: Pathogenic. The variant received 10 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, 5 uncertain in NM_001177316.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137233234-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

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.586G>T	p.Gly196Trp	missense	Exon 7 of 13	NP_001170787.2
	SLC34A3	NM_001177317.2		c.586G>T	p.Gly196Trp	missense	Exon 7 of 13	NP_001170788.2
	SLC34A3	NM_080877.3		c.586G>T	p.Gly196Trp	missense	Exon 7 of 13	NP_543153.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A3	ENST00000673835.1	MANE Select	c.586G>T	p.Gly196Trp	missense	Exon 7 of 13	ENSP00000501114.1
	SLC34A3	ENST00000361134.2	TSL:2	c.586G>T	p.Gly196Trp	missense	Exon 7 of 13	ENSP00000355353.2
	SLC34A3	ENST00000538474.5	TSL:5	c.586G>T	p.Gly196Trp	missense	Exon 7 of 13	ENSP00000442397.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000269 AC: 5 AN: 185974 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000301

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000843 AC: 12 AN: 1422966 Hom.: 0 Cov.: 36 AF XY: 0.00000851 AC XY: 6 AN XY: 704890

African (AFR) AF: 0.00 AC: 0 AN: 32422

American (AMR) AF: 0.00 AC: 0 AN: 39830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 37092

South Asian (SAS) AF: 0.00 AC: 0 AN: 82118

European-Finnish (FIN) AF: 0.000205 AC: 10 AN: 48882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092800

Other (OTH) AF: 0.0000170 AC: 1 AN: 58712

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.77
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.78		Gain of MoRF binding (P = 0.0868)
MVP		0.77
MPC		0.24
ClinPred		0.52	D
GERP RS		-1.3
Varity_R		0.62
gMVP		0.67
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs121918237; hg19: chr9-140127686;