chr13-28710761-T-A

Position:

chr13-28710761-T-A

Variant summary

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

The NM_181785.4(SLC46A3):c.1143A>T(p.Gln381His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,610,566 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SLC46A3
NM_181785.4 missense, splice_region

Scores

Splicing: ADA: 0.9789

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.41

Variant links:

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]

SLC46A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
SLC46A3	NM_181785.4 linkuse as main transcript	c.1143A>T	p.Gln381His	missense_variant, splice_region_variant	4/6	ENST00000266943.11	NP_861450.1	Q7Z3Q1-1A0A024RDN9
SLC46A3	NM_001135919.2 linkuse as main transcript	c.1143A>T	p.Gln381His	missense_variant, splice_region_variant	4/7		NP_001129391.1	Q7Z3Q1-2
SLC46A3	NM_001347960.2 linkuse as main transcript	c.1143A>T	p.Gln381His	missense_variant, splice_region_variant	4/6		NP_001334889.1	Q7Z3Q1-1A0A024RDN9
SLC46A3	XM_005266361.3 linkuse as main transcript	c.1143A>T	p.Gln381His	missense_variant, splice_region_variant	4/7		XP_005266418.1	Q7Z3Q1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC46A3	ENST00000266943.11 linkuse as main transcript	c.1143A>T	p.Gln381His	missense_variant, splice_region_variant	4/6	1	NM_181785.4	ENSP00000266943.7		Q7Z3Q1-1
SLC46A3	ENST00000380814.4 linkuse as main transcript	c.1143A>T	p.Gln381His	missense_variant, splice_region_variant	4/7	1		ENSP00000370192.4		Q7Z3Q1-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250752

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135526

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1458328

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725714

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.1143A>T (p.Q381H) alteration is located in exon 4 (coding exon 3) of the SLC46A3 gene. This alteration results from a A to T substitution at nucleotide position 1143, causing the glutamine (Q) at amino acid position 381 to be replaced by a histidine (H). 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

0.79

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.36

MutPred

0.77

Gain of catalytic residue at G382 (P = 0);Gain of catalytic residue at G382 (P = 0);

MVP

0.57

MPC

0.69

ClinPred

0.99

GERP RS

5.9

Varity_R

0.77

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.59

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over