13-28713270-T-C

Position:

• chr13-28713270-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181785.4(SLC46A3):​c.470A>G​(p.Asp157Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC46A3 NM_181785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A3	NM_181785.4	c.470A>G	p.Asp157Gly	missense_variant	3/6	ENST00000266943.11	NP_861450.1
SLC46A3	NM_001135919.2	c.470A>G	p.Asp157Gly	missense_variant	3/7		NP_001129391.1
SLC46A3	NM_001347960.2	c.470A>G	p.Asp157Gly	missense_variant	3/6		NP_001334889.1
SLC46A3	XM_005266361.3	c.470A>G	p.Asp157Gly	missense_variant	3/7		XP_005266418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC46A3	ENST00000266943.11	c.470A>G	p.Asp157Gly	missense_variant	3/6	1	NM_181785.4	ENSP00000266943.7
SLC46A3	ENST00000380814.4	c.470A>G	p.Asp157Gly	missense_variant	3/7	1		ENSP00000370192.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461680 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727118

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Jun 10, 2024

The c.470A>G (p.D157G) alteration is located in exon 3 (coding exon 2) of the SLC46A3 gene. This alteration results from a A to G substitution at nucleotide position 470, causing the aspartic acid (D) at amino acid position 157 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	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.81		Gain of catalytic residue at F152 (P = 2e-04);Gain of catalytic residue at F152 (P = 2e-04);
MVP		0.44
MPC		0.82
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.72
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr13-29287407;