5-33944713-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_016180.5(SLC45A2):c.1528A>G(p.Thr510Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC45A2 NM_016180.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_016180.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.10405779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC45A2	NM_016180.5	c.1528A>G	p.Thr510Ala	missense_variant	7/7	ENST00000296589.9
SLC45A2	XM_047417259.1	c.1288A>G	p.Thr430Ala	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC45A2	ENST00000296589.9	c.1528A>G	p.Thr510Ala	missense_variant	7/7	1	NM_016180.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251342 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.00000378

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2023

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. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 510 of the SLC45A2 protein (p.Thr510Ala). This variant is present in population databases (rs567138411, gnomAD 0.006%). 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: 1520375). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	13
Dann	Benign	0.83
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.70	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.12
Sift	Benign	0.50	T
Sift4G	Benign	0.36	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.43		Loss of glycosylation at T510 (P = 0.0224);
MVP		0.86
MPC		0.038
ClinPred		0.061	T
GERP RS		-1.5
Varity_R		0.062
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs567138411; hg19: chr5-33944818;