Genetic Variant NM_181785.4:c.1189G>A (chr13-28704055-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181785.4(SLC46A3):c.1189G>A(p.Val397Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

SLC46A3
NM_181785.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.02

Publications

0 publications found

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:

LOC124903143 (HGNC:):

LOC124903143 links:

RNU6-53P (HGNC:42543): (RNA, U6 small nuclear 53, pseudogene)

RNU6-53P links:

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ACMG classification

Classification was made for transcript

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=0.04332459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC46A3	NM_181785.4 link	c.1189G>A	p.Val397Ile	missense_variant	Exon 5 of 6	ENST00000266943.11	NP_861450.1	Q7Z3Q1-1A0A024RDN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC46A3	ENST00000266943.11 link	c.1189G>A	p.Val397Ile	missense_variant	Exon 5 of 6	1	NM_181785.4	ENSP00000266943.7	Q7Z3Q1-1
SLC46A3	ENST00000380814.4 link	c.1189G>A	p.Val397Ile	missense_variant	Exon 5 of 7	1		ENSP00000370192.4	Q7Z3Q1-2
SLC46A3	ENST00000475385.1 link	n.503G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
RNU6-53P	ENST00000365367.1 link	n.-248G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251240

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Prostate cancer

Uncertain:1

Science for Life laboratory, Karolinska Institutet

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L

PhyloP100

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.18

N;N

REVEL

Benign

0.030

Sift

Benign

0.82

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0040

B;B

Vest4

0.12

MutPred

0.33

Gain of catalytic residue at T393 (P = 0.0028);Gain of catalytic residue at T393 (P = 0.0028);

MVP

0.055

MPC

0.14

ClinPred

0.053

GERP RS

3.0

Varity_R

0.029

gMVP

0.067

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over