13-28713068-C-G

Variant names:

• chr13-28713068-C-G
• rs746121838
• NM_181785.4:c.672G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181785.4(SLC46A3):​c.672G>C​(p.Glu224Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC46A3 NM_181785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06629968).

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.672G>C	p.Glu224Asp	missense	Exon 3 of 6	NP_861450.1	Q7Z3Q1-1
	SLC46A3	NM_001135919.2		c.672G>C	p.Glu224Asp	missense	Exon 3 of 7	NP_001129391.1	Q7Z3Q1-2
	SLC46A3	NM_001347960.2		c.672G>C	p.Glu224Asp	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.672G>C	p.Glu224Asp	missense	Exon 3 of 6	ENSP00000266943.7	Q7Z3Q1-1
	SLC46A3	ENST00000380814.4	TSL:1	c.672G>C	p.Glu224Asp	missense	Exon 3 of 7	ENSP00000370192.4	Q7Z3Q1-2
	SLC46A3	ENST00000878132.1		c.759G>C	p.Glu253Asp	missense	Exon 4 of 7	ENSP00000548191.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458906 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725784

African (AFR) AF: 0.00 AC: 0 AN: 33152

American (AMR) AF: 0.00 AC: 0 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111426

Other (OTH) AF: 0.0000166 AC: 1 AN: 60250

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	Benign	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.0
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.094
Sift	Benign	0.55	T
Sift4G	Benign	0.41	T
Polyphen		0.35	B
Vest4		0.094
MutPred		0.46		Gain of catalytic residue at Q228 (P = 0)
MVP		0.23
MPC		0.16
ClinPred		0.091	T
GERP RS		0.25
Varity_R		0.048
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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

dbSNP: rs746121838; hg19: chr13-29287205;