6-25762026-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005495.3(SLC17A4):c.64G>A(p.Val22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC17A4 NM_005495.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.47

Genes affected

SLC17A4 (HGNC:10932): (solute carrier family 17 member 4) Phosphate homeostasis is maintained by regulating intake, intestinal absorption, bone deposition and resorption, and renal excretion of phosphate. The central molecule in the control of phosphate excretion from the kidney is the sodium/phosphate cotransporter NPT1 (SLC17A1; MIM 182308), which is located in the renal proximal tubule. NPT1 uses the transmembrane electrochemical potential gradient of sodium to transport phosphate across the cell membrane. SLC17A4 is a similar sodium/phosphate cotransporter in the intestinal mucosa that plays an important role in the absorption of phosphate from the intestine (summary by Shibui et al., 1999 [PubMed 10319585]).[supplied by OMIM, Feb 2011]

SLC17A1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035106838).
• BP6: Variant 6-25762026-G-A is Benign according to our data. Variant chr6-25762026-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2284159.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC17A4	NM_005495.3	c.64G>A	p.Val22Met	missense_variant	2/12	ENST00000377905.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A4	ENST00000377905.9	c.64G>A	p.Val22Met	missense_variant	2/12	1	NM_005495.3	P1
SLC17A4	ENST00000397076.2	c.-199G>A		5_prime_UTR_variant	1/7	2
SLC17A4	ENST00000439485.6	c.-199G>A		5_prime_UTR_variant	2/13	5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152062 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250758 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135530

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461140 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74400

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.014
Dann	Benign	0.053
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00062	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.021
Sift	Benign	0.44	T
Sift4G	Benign	0.36	T
Polyphen		0.21	B
Vest4		0.10
MutPred		0.31		Gain of disorder (P = 0.0606);
MVP		0.20
MPC		0.073
ClinPred		0.024	T
GERP RS		-8.5
Varity_R		0.021
gMVP		0.073

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

Publications

LitVar

Other links and lift over

dbSNP: rs576691816; hg19: chr6-25762254;