5-33951628-A-T

Variant names:

• chr5-33951628-A-T
• NM_016180.5:c.1082T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_016180.5(SLC45A2):​c.1082T>A​(p.Leu361His) 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. 14/21 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. L361P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC45A2 NM_016180.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25

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 topological_domain Extracellular (size 26) in uniprot entity S45A2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_016180.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-33951628-A-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.22342998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC45A2	NM_016180.5	c.1082T>A	p.Leu361His	missense_variant	Exon 5 of 7	ENST00000296589.9	NP_057264.4
SLC45A2	NM_001012509.4	c.1082T>A	p.Leu361His	missense_variant	Exon 5 of 6		NP_001012527.2
SLC45A2	XM_047417259.1	c.842T>A	p.Leu281His	missense_variant	Exon 5 of 7		XP_047273215.1
SLC45A2	NM_001297417.4	c.*24T>A		3_prime_UTR_variant	Exon 4 of 4		NP_001284346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000296589.9	c.1082T>A	p.Leu361His	missense_variant	Exon 5 of 7	1	NM_016180.5	ENSP00000296589.4
SLC45A2	ENST00000382102.7	c.1082T>A	p.Leu361His	missense_variant	Exon 5 of 6	1		ENSP00000371534.3
SLC45A2	ENST00000509381	c.*24T>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000421100.1
SLC45A2	ENST00000510600.1	c.557T>A	p.Leu186His	missense_variant	Exon 4 of 5	3		ENSP00000424010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.29
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.61	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.013	B;B;.
Vest4		0.44
MutPred		0.56		Gain of disorder (P = 0.0068);Gain of disorder (P = 0.0068);.;
MVP		0.91
MPC		0.048
ClinPred		0.37	T
GERP RS		5.9
Varity_R		0.24
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-33951733;