chr5-33954406-T-A

Variant names:

• chr5-33954406-T-A
• rs2287949
• ENST00000509381.1:c.661A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001297417.4(SLC45A2):​c.661A>T​(p.Ser221Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S221G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC45A2 NM_001297417.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.36

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 transmembrane_region Helical; Name=6 (size 20) in uniprot entity S45A2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001297417.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05858943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC45A2	NM_016180.5	c.987A>T	p.Thr329Thr	synonymous_variant	Exon 4 of 7	ENST00000296589.9	NP_057264.4
SLC45A2	NM_001297417.4	c.661A>T	p.Ser221Cys	missense_variant	Exon 3 of 4		NP_001284346.2
SLC45A2	NM_001012509.4	c.987A>T	p.Thr329Thr	synonymous_variant	Exon 4 of 6		NP_001012527.2
SLC45A2	XM_047417259.1	c.747A>T	p.Thr249Thr	synonymous_variant	Exon 4 of 7		XP_047273215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000509381.1	c.661A>T	p.Ser221Cys	missense_variant	Exon 3 of 4	1		ENSP00000421100.1
SLC45A2	ENST00000296589.9	c.987A>T	p.Thr329Thr	synonymous_variant	Exon 4 of 7	1	NM_016180.5	ENSP00000296589.4
SLC45A2	ENST00000382102.7	c.987A>T	p.Thr329Thr	synonymous_variant	Exon 4 of 6	1		ENSP00000371534.3
SLC45A2	ENST00000510600.1	c.462A>T	p.Thr154Thr	synonymous_variant	Exon 3 of 5	3		ENSP00000424010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461738 Hom.: 0 Cov.: 67 AF XY: 0.00 AC XY: 0 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.18
DANN	Benign	0.85
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.24		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.19
ClinPred		0.056	T
GERP RS		-9.5

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: rs2287949; hg19: chr5-33954511;