6-25762001-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005495.3(SLC17A4):c.39C>A(p.Asp13Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000523 in 1,613,268 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D13Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: SLC17A4 NM_005495.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.31

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006346971).
• BP6: Variant 6-25762001-C-A is Benign according to our data. Variant chr6-25762001-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2352093.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC17A4	NM_005495.3	c.39C>A	p.Asp13Glu	missense_variant	2/12	ENST00000377905.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A4	ENST00000377905.9	c.39C>A	p.Asp13Glu	missense_variant	2/12	1	NM_005495.3	P1
SLC17A4	ENST00000397076.2	c.-224C>A		5_prime_UTR_variant	1/7	2
SLC17A4	ENST00000439485.6	c.-224C>A		5_prime_UTR_variant	2/13	5

Frequencies

GnomAD3 genomes AF: 0.000566 AC: 86 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00410

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000494 AC: 124 AN: 251004 Hom.: 1 AF XY: 0.000413 AC XY: 56 AN XY: 135656

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000518 AC: 757 AN: 1461104 Hom.: 2 Cov.: 30 AF XY: 0.000526 AC XY: 382 AN XY: 726870

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000491

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74394

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00410

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.000895

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000545

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.39C>A (p.D13E) alteration is located in exon 2 (coding exon 1) of the SLC17A4 gene. This alteration results from a C to A substitution at nucleotide position 39, causing the aspartic acid (D) at amino acid position 13 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

SLC17A4: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.016
Dann	Benign	0.28
DEOGEN2	Benign	0.015	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.041
Sift	Benign	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.30		Loss of helix (P = 0.0196);
MVP		0.14
MPC		0.069
ClinPred		0.0090	T
GERP RS		-8.5
Varity_R		0.026
gMVP		0.051

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs150942022; hg19: chr6-25762229;