rs121912621

Variant names:

• chr5-33982329-C-T
• rs121912621
• NM_016180.5:c.469G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-33982329-C-T
• chr5-33982329-C-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_016180.5(SLC45A2):​c.469G>A​(p.Asp157Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D157E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SLC45A2 NM_016180.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.71
• Publications: 17 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr5-33982327-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1800731.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 5-33982329-C-T is Pathogenic according to our data. Variant chr5-33982329-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4503.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.469G>A	p.Asp157Asn	missense	Exon 2 of 7	NP_057264.4
	SLC45A2	NM_001012509.4		c.469G>A	p.Asp157Asn	missense	Exon 2 of 6	NP_001012527.2	Q9UMX9-4
	SLC45A2	NM_001297417.4		c.469G>A	p.Asp157Asn	missense	Exon 2 of 4	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.469G>A	p.Asp157Asn	missense	Exon 2 of 7	ENSP00000296589.4	Q9UMX9-1
	SLC45A2	ENST00000382102.7	TSL:1	c.469G>A	p.Asp157Asn	missense	Exon 2 of 6	ENSP00000371534.3	Q9UMX9-4
	SLC45A2	ENST00000509381.1	TSL:1	c.469G>A	p.Asp157Asn	missense	Exon 2 of 4	ENSP00000421100.1	D6RGY6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251482 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727240

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

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000254 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.88		Loss of stability (P = 0.1448)
MVP		0.97
MPC		0.27
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.90
Mutation Taster		=4/96	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

Other links and lift over

dbSNP: rs121912621; hg19: chr5-33982434; COSMIC: COSV99672894; COSMIC: COSV99672894;