17-68269191-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004694.5(SLC16A6):c.1477C>T(p.Arg493Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,420,450 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000069 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00011 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC16A6 NM_004694.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0100

Genes affected

SLC16A6 (HGNC:10927): (solute carrier family 16 member 6) Predicted to enable monocarboxylic acid transmembrane transporter activity. Predicted to be involved in monocarboxylic acid transport. Predicted to be located in membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARSG (HGNC:24102): (arylsulfatase G) The protein encoded by this gene belongs to the sulfatase enzyme family. Sulfatases hydrolyze sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules. This protein displays arylsulfatase activity at acidic pH, as is typical of lysosomal sulfatases, and has been shown to localize in the lysosomes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043620825).
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A6	NM_004694.5	c.1477C>T	p.Arg493Cys	missense_variant	6/6	ENST00000580666.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A6	ENST00000580666.6	c.1477C>T	p.Arg493Cys	missense_variant	6/6	1	NM_004694.5	P1
SLC16A6	ENST00000327268.8	c.1477C>T	p.Arg493Cys	missense_variant	7/7	1		P1
ARSG	ENST00000448504.6	c.-552+9765G>A		intron_variant		1		P1
ARSG	ENST00000578726.1	n.27-4699G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000687 AC: 10 AN: 145544 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000716

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00181

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 32 AN: 217600 Hom.: 2 AF XY: 0.000220 AC XY: 26 AN XY: 117948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.0000504

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 150 AN: 1420450 Hom.: 4 Cov.: 28 AF XY: 0.000166 AC XY: 117 AN XY: 704530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000254

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00167

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00000459

Gnomad4 OTH exome AF: 0.0000682

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000687 AC: 10 AN: 145660 Hom.: 0 Cov.: 27 AF XY: 0.0000990 AC XY: 7 AN XY: 70734

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000715

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00181

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000149

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000133 AC: 16

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 17, 2024

The c.1477C>T (p.R493C) alteration is located in exon 7 (coding exon 5) of the SLC16A6 gene. This alteration results from a C to T substitution at nucleotide position 1477, causing the arginine (R) at amino acid position 493 to be replaced by a cysteine (C). 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	Benign	0.097
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.050	T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.25
MVP		0.33
MPC		2.7
ClinPred		0.19	T
GERP RS		2.8
Varity_R		0.092
gMVP		0.56

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: rs782242193; hg19: chr17-66265332;