chr6-25861672-A-C

Position:

• chr6-25861672-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001098486.2(SLC17A3):​c.577T>G​(p.Trp193Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,776 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC17A3 NM_001098486.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81

Genes affected

SLC17A3 (HGNC:10931): (solute carrier family 17 member 3) The protein encoded by this gene is a voltage-driven transporter that excretes intracellular urate and organic anions from the blood into renal tubule cells. Two transcript variants encoding different isoforms have been found for this gene. The longer isoform is a plasma membrane protein with transporter activity while the shorter isoform localizes to the endoplasmic reticulum. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC17A3	NM_001098486.2	c.577T>G	p.Trp193Gly	missense_variant	5/13	ENST00000397060.8
SLC17A3	NM_006632.4	c.343T>G	p.Trp115Gly	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A3	ENST00000397060.8	c.577T>G	p.Trp193Gly	missense_variant	5/13	2	NM_001098486.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.343T>G (p.W115G) alteration is located in exon 4 (coding exon 3) of the SLC17A3 gene. This alteration results from a T to G substitution at nucleotide position 343, causing the tryptophan (W) at amino acid position 115 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Uncertain	0.62	.;D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	3.6	.;H;H
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-13	D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.80
MutPred		0.86		.;Gain of disorder (P = 0.0029);Gain of disorder (P = 0.0029);
MVP		0.72
MPC		0.29
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.58
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1765449230; hg19: chr6-25861900;