Variant 13-28703944-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_181785.4(SLC46A3):c.1300T>C(p.Cys434Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 1 hom. )

Consequence

SLC46A3
NM_181785.4 missense, splice_region

Scores

Splicing: ADA: 0.001522

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18

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:

SLC46A3 (HGNC:):

SLC46A3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A3	NM_181785.4 linkuse as main transcript	c.1300T>C	p.Cys434Arg	missense_variant, splice_region_variant	5/6	ENST00000266943.11	NP_861450.1	Q7Z3Q1-1A0A024RDN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC46A3	ENST00000266943.11 linkuse as main transcript	c.1300T>C	p.Cys434Arg	missense_variant, splice_region_variant	5/6	1	NM_181785.4	ENSP00000266943.7	Q7Z3Q1-1
SLC46A3	ENST00000380814.4 linkuse as main transcript	c.1300T>C	p.Cys434Arg	missense_variant, splice_region_variant	5/7	1		ENSP00000370192.4	Q7Z3Q1-2
SLC46A3	ENST00000475385.1 linkuse as main transcript	n.614T>C		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460912

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726786

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

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

Nov 18, 2022

The c.1300T>C (p.C434R) alteration is located in exon 5 (coding exon 4) of the SLC46A3 gene. This alteration results from a T to C substitution at nucleotide position 1300, causing the cysteine (C) at amino acid position 434 to be replaced by an arginine (R). 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

Uncertain

0.45

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.032

T;.

Eigen

Benign

-0.096

Eigen_PC

Benign

-0.098

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.093

T;T

Sift4G

Benign

0.068

T;T

Polyphen

0.58

P;P

Vest4

0.77

MutPred

0.67

Gain of catalytic residue at C434 (P = 0.0037);Gain of catalytic residue at C434 (P = 0.0037);

MVP

0.46

MPC

0.46

ClinPred

0.42

GERP RS

3.1

Varity_R

0.35

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.048

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

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