5-33947179-C-T

Position:

chr5-33947179-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016180.5(SLC45A2):c.1352G>A(p.Arg451His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000789 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 1 hom. )

Consequence

SLC45A2
NM_016180.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.0540

Variant links:

Genes affected

SLC45A2 (HGNC:16472): (solute carrier family 45 member 2) This gene encodes a transporter protein that mediates melanin synthesis. The protein is expressed in a high percentage of melanoma cell lines. Mutations in this gene are a cause of oculocutaneous albinism type 4, and polymorphisms in this gene are associated with variations in skin and hair color. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SLC45A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006589085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC45A2	NM_016180.5 linkuse as main transcript	c.1352G>A	p.Arg451His	missense_variant	6/7	ENST00000296589.9	NP_057264.4	Q9UMX9-1A0A076YGN1A0A076YIB8
SLC45A2	NM_001012509.4 linkuse as main transcript	c.1352G>A	p.Arg451His	missense_variant	6/6		NP_001012527.2	Q9UMX9-4
SLC45A2	XM_047417259.1 linkuse as main transcript	c.1112G>A	p.Arg371His	missense_variant	6/7		XP_047273215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000296589.9 linkuse as main transcript	c.1352G>A	p.Arg451His	missense_variant	6/7	1	NM_016180.5	ENSP00000296589.4		Q9UMX9-1
SLC45A2	ENST00000382102.7 linkuse as main transcript	c.1352G>A	p.Arg451His	missense_variant	6/6	1		ENSP00000371534.3		Q9UMX9-4

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000716

AC:

180

AN:

251482

Hom.:

AF XY:

0.000750

AC XY:

102

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000812

AC:

1187

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

583

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000907

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000571

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000811

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000840

AC:

102

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 451 of the SLC45A2 protein (p.Arg451His). This variant is present in population databases (rs142680641, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SLC45A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 284405). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC45A2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2024	Identified in the heterozygous state in families with cutaneous melanoma; however, the variant did not always segregate with affected family members, and two families also harbored a variant in the TYRP1 gene (PMID: 31233279); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31233279, 27019209) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 20, 2017

- -

Oculocutaneous albinism type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 18, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.0066

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.13

Sift

Benign

0.20

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0010

B;B

Vest4

0.19

MVP

0.77

MPC

0.044

ClinPred

0.0097

GERP RS

0.10

Varity_R

0.042

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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