13-28713319-A-C

Position:

• chr13-28713319-A-C

Variant summary

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

The NM_181785.4(SLC46A3):​c.421T>G​(p.Cys141Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC46A3 NM_181785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21068674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A3	NM_181785.4	c.421T>G	p.Cys141Gly	missense_variant	3/6	ENST00000266943.11	NP_861450.1
SLC46A3	NM_001135919.2	c.421T>G	p.Cys141Gly	missense_variant	3/7		NP_001129391.1
SLC46A3	NM_001347960.2	c.421T>G	p.Cys141Gly	missense_variant	3/6		NP_001334889.1
SLC46A3	XM_005266361.3	c.421T>G	p.Cys141Gly	missense_variant	3/7		XP_005266418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC46A3	ENST00000266943.11	c.421T>G	p.Cys141Gly	missense_variant	3/6	1	NM_181785.4	ENSP00000266943.7
SLC46A3	ENST00000380814.4	c.421T>G	p.Cys141Gly	missense_variant	3/7	1		ENSP00000370192.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Feb 17, 2022

The c.421T>G (p.C141G) alteration is located in exon 3 (coding exon 2) of the SLC46A3 gene. This alteration results from a T to G substitution at nucleotide position 421, causing the cysteine (C) at amino acid position 141 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0042
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.081
Sift	Benign	0.40	T;T
Sift4G	Uncertain	0.039	D;D
Polyphen		0.0070	B;B
Vest4		0.21
MutPred		0.47		Gain of catalytic residue at N143 (P = 2e-04);Gain of catalytic residue at N143 (P = 2e-04);
MVP		0.24
MPC		0.22
ClinPred		0.82	D
GERP RS		5.0
Varity_R		0.22
gMVP		0.55

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: chr13-29287456;