13-28713288-C-T

Variant names:

• chr13-28713288-C-T
• NM_181785.4:c.452G>A

Variant summary

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

The NM_181785.4(SLC46A3):​c.452G>A​(p.Cys151Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SLC46A3 NM_181785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

Genes affected

SLC46A3 (HGNC:27501): (solute carrier family 46 member 3) The protein encoded by this gene is a member of a transmembrane protein family that transports small molecules across membranes. The encoded protein has been found in lysosomal membranes, where it can transport catabolites from the lysosomes to the cytoplasm. This protein has been shown to be an effective transporter of the cytotoxic drug maytansine, which is used in antibody-based targeting of cancer cells. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC46A3	NM_181785.4	c.452G>A	p.Cys151Tyr	missense_variant	Exon 3 of 6	ENST00000266943.11	NP_861450.1
SLC46A3	NM_001135919.2	c.452G>A	p.Cys151Tyr	missense_variant	Exon 3 of 7		NP_001129391.1
SLC46A3	NM_001347960.2	c.452G>A	p.Cys151Tyr	missense_variant	Exon 3 of 6		NP_001334889.1
SLC46A3	XM_005266361.3	c.452G>A	p.Cys151Tyr	missense_variant	Exon 3 of 7		XP_005266418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC46A3	ENST00000266943.11	c.452G>A	p.Cys151Tyr	missense_variant	Exon 3 of 6	1	NM_181785.4	ENSP00000266943.7
SLC46A3	ENST00000380814.4	c.452G>A	p.Cys151Tyr	missense_variant	Exon 3 of 7	1		ENSP00000370192.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461670 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727108

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: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.452G>A (p.C151Y) alteration is located in exon 3 (coding exon 2) of the SLC46A3 gene. This alteration results from a G to A substitution at nucleotide position 452, causing the cysteine (C) at amino acid position 151 to be replaced by a tyrosine (Y). 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	0.86
BayesDel_addAF	Benign	0.0068	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.61	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.96	D;P
Vest4		0.54
MutPred		0.64		Gain of catalytic residue at A150 (P = 0);Gain of catalytic residue at A150 (P = 0);
MVP		0.27
MPC		0.89
ClinPred		0.85	D
GERP RS		2.5
Varity_R		0.57
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-29287425;