17-82237416-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004207.4(SLC16A3):c.646C>T(p.Arg216Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,570,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SLC16A3 NM_004207.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

Genes affected

SLC16A3 (HGNC:10924): (solute carrier family 16 member 3) Lactic acid and pyruvate transport across plasma membranes is catalyzed by members of the proton-linked monocarboxylate transporter (MCT) family, which has been designated solute carrier family-16. Each MCT appears to have slightly different substrate and inhibitor specificities and transport kinetics, which are related to the metabolic requirements of the tissues in which it is found. The MCTs, which include MCT1 (SLC16A1; MIM 600682) and MCT2 (SLC16A7; MIM 603654), are characterized by 12 predicted transmembrane domains (Price et al., 1998 [PubMed 9425115]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2081053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A3	NM_004207.4	c.646C>T	p.Arg216Cys	missense_variant	4/5	ENST00000582743.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A3	ENST00000582743.6	c.646C>T	p.Arg216Cys	missense_variant	4/5	1	NM_004207.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000160 AC: 29 AN: 181312 Hom.: 0 AF XY: 0.000221 AC XY: 22 AN XY: 99680

Gnomad AFR exome AF: 0.0000989

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000492

Gnomad FIN exome AF: 0.0000728

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000150 AC: 213 AN: 1418526 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 123 AN XY: 702420

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.0000219

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000119

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74360

Gnomad4 AFR AF: 0.000121

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000894 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000849 AC: 10

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

Jun 17, 2022

The c.646C>T (p.R216C) alteration is located in exon 4 (coding exon 3) of the SLC16A3 gene. This alteration results from a C to T substitution at nucleotide position 646, causing the arginine (R) at amino acid position 216 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	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Benign	0.95
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;.;.;.;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.53	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;D;.;.;D;D;D;.;D;.
Vest4		0.59, 0.60, 0.59, 0.65
MutPred		0.63		Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);.;Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);Loss of disorder (P = 0.0141);.;
MVP		0.68
MPC		0.98
ClinPred		0.16	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.59

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: rs750915194; hg19: chr17-80195292;