17-82236199-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004207.4(SLC16A3):c.191C>T(p.Ser64Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,660 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC16A3 NM_004207.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A3	NM_004207.4	c.191C>T	p.Ser64Phe	missense_variant	2/5	ENST00000582743.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A3	ENST00000582743.6	c.191C>T	p.Ser64Phe	missense_variant	2/5	1	NM_004207.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250268 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460660 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 13, 2022

The c.191C>T (p.S64F) alteration is located in exon 2 (coding exon 1) of the SLC16A3 gene. This alteration results from a C to T substitution at nucleotide position 191, causing the serine (S) at amino acid position 64 to be replaced by a phenylalanine (F). 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	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	30
Dann	Uncertain	0.98
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;.;D;D;D;.;.;D;.;D;D;.
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;D;.;.;.;D;D;.;D;.;.;D
Vest4		0.94, 0.94, 0.94, 0.90, 0.92
MutPred		0.47		Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);.;Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);Loss of catalytic residue at S64 (P = 0.0876);
MVP		0.81
MPC		1.0
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.85
gMVP		0.97

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: rs925306842; hg19: chr17-80194075;