5-33944624-T-G

Position:

• chr5-33944624-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016180.5(SLC45A2):​c.*24A>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,611,258 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (99 hom.)
• Consequence: SLC45A2 NM_016180.5 splice_region
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.151

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-33944624-T-G is Benign according to our data. Variant chr5-33944624-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 906956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00204 (311/152274) while in subpopulation SAS AF= 0.0345 (166/4816). AF 95% confidence interval is 0.0302. There are 7 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC45A2	NM_016180.5	c.*24A>C		splice_region_variant	7/7	ENST00000296589.9	NP_057264.4
SLC45A2	NM_016180.5	c.*24A>C		3_prime_UTR_variant	7/7	ENST00000296589.9	NP_057264.4
SLC45A2	XM_047417259.1	c.*24A>C		splice_region_variant	7/7		XP_047273215.1
SLC45A2	XM_047417259.1	c.*24A>C		3_prime_UTR_variant	7/7		XP_047273215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000296589.9	c.*24A>C		splice_region_variant	7/7	1	NM_016180.5	ENSP00000296589.4
SLC45A2	ENST00000296589	c.*24A>C		3_prime_UTR_variant	7/7	1	NM_016180.5	ENSP00000296589.4

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152156 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00571 AC: 1417 AN: 248050 Hom.: 35 AF XY: 0.00773 AC XY: 1037 AN XY: 134172

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0375

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00610

GnomAD4 exome AF: 0.00336 AC: 4903 AN: 1458984 Hom.: 99 Cov.: 31 AF XY: 0.00452 AC XY: 3278 AN XY: 725850

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000997

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0365

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.00418

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152274 Hom.: 7 Cov.: 33 AF XY: 0.00250 AC XY: 186 AN XY: 74466

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0345

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00184 Hom.: 1

Bravo AF: 0.00114

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oculocutaneous albinism type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.69

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: rs45552240; hg19: chr5-33944729; COSMIC: COSV56871857; COSMIC: COSV56871857;