rs387906318

Variant names:

• chr5-33963914-GAGA-G
• rs387906318
• NM_016180.5:c.662_664delTCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_016180.5(SLC45A2):​c.662_664delTCT​(p.Phe221del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SLC45A2 NM_016180.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.43
• Publications: 3 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: PanelApp Australia, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_016180.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 5-33963914-GAGA-G is Pathogenic according to our data. Variant chr5-33963914-GAGA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC45A2	NM_016180.5	MANE Select	c.662_664delTCT	p.Phe221del	disruptive_inframe_deletion	Exon 3 of 7	NP_057264.4
	SLC45A2	NM_001012509.4		c.662_664delTCT	p.Phe221del	disruptive_inframe_deletion	Exon 3 of 6	NP_001012527.2	Q9UMX9-4
	SLC45A2	NM_001297417.4		c.563-9413_563-9411delTCT		intron	N/A	NP_001284346.2	D6RGY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC45A2	ENST00000296589.9	TSL:1 MANE Select	c.662_664delTCT	p.Phe221del	disruptive_inframe_deletion	Exon 3 of 7	ENSP00000296589.4	Q9UMX9-1
	SLC45A2	ENST00000382102.7	TSL:1	c.662_664delTCT	p.Phe221del	disruptive_inframe_deletion	Exon 3 of 6	ENSP00000371534.3	Q9UMX9-4
	SLC45A2	ENST00000509381.1	TSL:1	c.563-9413_563-9411delTCT		intron	N/A	ENSP00000421100.1	D6RGY6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461876 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Oculocutaneous albinism type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=47/53	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387906318;

hg19: chr5-33964019;