chr5-33951628-A-T

Variant names:

• chr5-33951628-A-T
• rs121912619
• NM_016180.5:c.1082T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. 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. 14/22 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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 ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4499.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22342998).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016180.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC45A2	NM_016180.5	MANE Select	c.1082T>A	p.Leu361His	missense	Exon 5 of 7	NP_057264.4
	SLC45A2	NM_001012509.4		c.1082T>A	p.Leu361His	missense	Exon 5 of 6	NP_001012527.2
	SLC45A2	NM_001297417.4		c.*24T>A		3_prime_UTR	Exon 4 of 4	NP_001284346.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC45A2	ENST00000296589.9	TSL:1 MANE Select	c.1082T>A	p.Leu361His	missense	Exon 5 of 7	ENSP00000296589.4
	SLC45A2	ENST00000382102.7	TSL:1	c.1082T>A	p.Leu361His	missense	Exon 5 of 6	ENSP00000371534.3
	SLC45A2	ENST00000509381.1	TSL:1	c.*24T>A		3_prime_UTR	Exon 4 of 4	ENSP00000421100.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.40
Sift	Benign	0.61	T
Sift4G	Benign	0.62	T
Polyphen		0.013	B
Vest4		0.44
MutPred		0.56		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
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs121912619; hg19: chr5-33951733;