rs769409705

Positions:

• chr5-177386492-G-A
• chr5-177386492-G-C
• chr5-177386492-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_003052.5(SLC34A1):​c.458G>A​(p.Gly153Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. G153V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC34A1 NM_003052.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.19

Genes affected

SLC34A1 (HGNC:11019): (solute carrier family 34 member 1) Enables sodium:phosphate symporter activity. Involved in several processes, including phosphate ion homeostasis; phosphate ion transport; and response to lead ion. Located in several cellular components, including apical plasma membrane; mitotic spindle; and nuclear speck. Implicated in several diseases, including Fanconi syndrome (multiple); chronic kidney disease; hereditary hypophosphatemic rickets with hypercalciuria; hypophosphatemic nephrolithiasis/osteoporosis 1; and nephrolithiasis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical; Name=M2 (size 17) in uniprot entity NPT2A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_003052.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177386492-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC34A1	NM_003052.5	c.458G>A	p.Gly153Glu	missense_variant	5/13	ENST00000324417.6
SLC34A1	NM_001167579.2	c.458G>A	p.Gly153Glu	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC34A1	ENST00000324417.6	c.458G>A	p.Gly153Glu	missense_variant	5/13	1	NM_003052.5	P1
SLC34A1	ENST00000512593.5	c.458G>A	p.Gly153Glu	missense_variant	5/9	2
SLC34A1	ENST00000507685.5	n.542G>A		non_coding_transcript_exon_variant	5/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.90		Gain of catalytic residue at G153 (P = 0.078);Gain of catalytic residue at G153 (P = 0.078);
MVP		0.94
MPC		0.46
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs769409705; hg19: chr5-176813493;