5-33947306-C-T

Position:

• chr5-33947306-C-T

Variant summary

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

The NM_016180.5(SLC45A2):​c.1225G>A​(p.Gly409Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC45A2 NM_016180.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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 4 ACMG points.

• PM1: In a transmembrane_region Helical; Name=9 (size 20) in uniprot entity S45A2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_016180.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC45A2	NM_016180.5	c.1225G>A	p.Gly409Ser	missense_variant	6/7	ENST00000296589.9
SLC45A2	NM_001012509.4	c.1225G>A	p.Gly409Ser	missense_variant	6/6
SLC45A2	XM_047417259.1	c.985G>A	p.Gly329Ser	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC45A2	ENST00000296589.9	c.1225G>A	p.Gly409Ser	missense_variant	6/7	1	NM_016180.5	P1
SLC45A2	ENST00000382102.7	c.1225G>A	p.Gly409Ser	missense_variant	6/6	1
SLC45A2	ENST00000510600.1	c.700G>A	p.Gly234Ser	missense_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 17, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N;D
REVEL	Pathogenic	0.79
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.41	T;T;D
Polyphen		0.60	P;D;.
Vest4		0.84
MutPred		0.58		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;
MVP		0.96
MPC		0.23
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.30
gMVP		0.92

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: rs1554054057; hg19: chr5-33947411;