6-25849392-A-T

Variant names:

• chr6-25849392-A-T
• rs942379
• NM_001098486.2:c.1344T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001098486.2(SLC17A3):​c.1344T>A​(p.Ser448Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,607,540 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC17A3 NM_001098486.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.632
• Publications: 32 publications found

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]

SLC17A3 Gene-Disease associations (from GenCC):

• uric acid concentration, serum, quantitative trait locus 4

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

LOC124901285 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098486.2. 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
	SLC17A3	NM_001098486.2	MANE Select	c.1344T>A	p.Ser448Arg	missense	Exon 11 of 13	NP_001091956.1	O00476-2
	SLC17A3	NM_006632.4		c.1110T>A	p.Ser370Arg	missense	Exon 10 of 12	NP_006623.2	O00476-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A3	ENST00000397060.8	TSL:2 MANE Select	c.1344T>A	p.Ser448Arg	missense	Exon 11 of 13	ENSP00000380250.4	O00476-2
	SLC17A3	ENST00000361703.10	TSL:1	c.1110T>A	p.Ser370Arg	missense	Exon 10 of 12	ENSP00000355307.6	O00476-1
	SLC17A3	ENST00000861066.1		c.1344T>A	p.Ser448Arg	missense	Exon 11 of 14	ENSP00000531125.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455660 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724678

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106556

Other (OTH) AF: 0.00 AC: 0 AN: 60200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74160

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67954

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

Alfa AF: 0.00 Hom.: 52796

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.2
DANN	Benign	0.95
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.028	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.63
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.049	D
Polyphen		0.84	P
Vest4		0.50
MutPred		0.75		Gain of methylation at S370 (P = 0.01)
MVP		0.44
MPC		0.072
ClinPred		0.38	T
GERP RS		-0.84
PromoterAI		-0.016	Neutral
Varity_R		0.20
gMVP		0.73
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs942379; hg19: chr6-25849620;