chr13-28713288-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181785.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC46A3	NM_181785.4	MANE Select	c.452G>A	p.Cys151Tyr	missense	Exon 3 of 6	NP_861450.1	Q7Z3Q1-1
	SLC46A3	NM_001135919.2		c.452G>A	p.Cys151Tyr	missense	Exon 3 of 7	NP_001129391.1	Q7Z3Q1-2
	SLC46A3	NM_001347960.2		c.452G>A	p.Cys151Tyr	missense	Exon 3 of 6	NP_001334889.1	Q7Z3Q1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC46A3	ENST00000266943.11	TSL:1 MANE Select	c.452G>A	p.Cys151Tyr	missense	Exon 3 of 6	ENSP00000266943.7	Q7Z3Q1-1
	SLC46A3	ENST00000380814.4	TSL:1	c.452G>A	p.Cys151Tyr	missense	Exon 3 of 7	ENSP00000370192.4	Q7Z3Q1-2
	SLC46A3	ENST00000878132.1		c.539G>A	p.Cys180Tyr	missense	Exon 4 of 7	ENSP00000548191.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.2
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.029	D
Polyphen		0.96	D
Vest4		0.54
MutPred		0.64		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
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

hg19: chr13-29287425;