9-137234634-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001177316.2(SLC34A3):​c.1238C>T​(p.Ala413Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,612,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A413E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SLC34A3 NM_001177316.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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: Likely_pathogenic. The variant received 8 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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>T	p.Ala413Val	missense	Exon 12 of 13	NP_001170787.2	Q8N130
	SLC34A3	NM_001177317.2		c.1238C>T	p.Ala413Val	missense	Exon 12 of 13	NP_001170788.2	Q8N130
	SLC34A3	NM_080877.3		c.1238C>T	p.Ala413Val	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>T	p.Ala413Val	missense	Exon 12 of 13	ENSP00000501114.1	Q8N130
	SLC34A3	ENST00000361134.2	TSL:2	c.1238C>T	p.Ala413Val	missense	Exon 12 of 13	ENSP00000355353.2	Q8N130
	SLC34A3	ENST00000538474.5	TSL:5	c.1238C>T	p.Ala413Val	missense	Exon 12 of 13	ENSP00000442397.1	Q8N130

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000322 AC: 8 AN: 248528 AF XY: 0.0000444

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460196 Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11 AN XY: 726428

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

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

European-Finnish (FIN) AF: 0.0000578 AC: 3 AN: 51942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111890

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000305 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000578 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive hypophosphatemic bone disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.72
Sift	Benign	0.25	T
Sift4G	Benign	0.35	T
Polyphen		0.99	D
Vest4		0.88
MVP		0.76
MPC		0.29
ClinPred		0.46	T
GERP RS		3.6
Varity_R		0.34
gMVP		0.75
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;