17-82237290-T-G

Variant summary

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

The NM_004207.4(SLC16A3):c.520T>G(p.Tyr174Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC16A3 NM_004207.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 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, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A3	NM_004207.4	c.520T>G	p.Tyr174Asp	missense_variant	4/5	ENST00000582743.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A3	ENST00000582743.6	c.520T>G	p.Tyr174Asp	missense_variant	4/5	1	NM_004207.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1409738 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 696676

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000472 Hom.: 0

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

Aug 14, 2023

The c.520T>G (p.Y174D) alteration is located in exon 4 (coding exon 3) of the SLC16A3 gene. This alteration results from a T to G substitution at nucleotide position 520, causing the tyrosine (Y) at amino acid position 174 to be replaced by an aspartic acid (D). 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	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Benign	0.93
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D;D;.;T;D;D;.;.;.;D;.;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;D;.;.;.;D;D;D;.;D;.
Vest4		0.89, 0.89, 0.85
MutPred		0.85		Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);.;.;Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);Loss of methylation at R177 (P = 0.0467);.;
MVP		0.59
MPC		1.3
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.91

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: rs2050627554; hg19: chr17-80195166;