5-33954406-T-C

Variant names:

• chr5-33954406-T-C
• rs2287949
• ENST00000509381.1:c.661A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000509381.1(SLC45A2):​c.661A>G​(p.Ser221Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,613,992 control chromosomes in the GnomAD database, including 740,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S221A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.94 (67524 hom., cov: 32)
  • Exomes 𝑓: 0.95 (672762 hom.)
• Consequence: SLC45A2 ENST00000509381.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.36
• Publications: 33 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0415114E-7).
• BP6: Variant 5-33954406-T-C is Benign according to our data. Variant chr5-33954406-T-C is described in ClinVar as Benign. ClinVar VariationId is 197309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC45A2	NM_016180.5	c.987A>G	p.Thr329Thr	synonymous_variant	Exon 4 of 7	ENST00000296589.9	NP_057264.4
SLC45A2	NM_001297417.4	c.661A>G	p.Ser221Gly	missense_variant	Exon 3 of 4		NP_001284346.2
SLC45A2	NM_001012509.4	c.987A>G	p.Thr329Thr	synonymous_variant	Exon 4 of 6		NP_001012527.2
SLC45A2	XM_047417259.1	c.747A>G	p.Thr249Thr	synonymous_variant	Exon 4 of 7		XP_047273215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000509381.1	c.661A>G	p.Ser221Gly	missense_variant	Exon 3 of 4	1		ENSP00000421100.1
SLC45A2	ENST00000296589.9	c.987A>G	p.Thr329Thr	synonymous_variant	Exon 4 of 7	1	NM_016180.5	ENSP00000296589.4
SLC45A2	ENST00000382102.7	c.987A>G	p.Thr329Thr	synonymous_variant	Exon 4 of 6	1		ENSP00000371534.3
SLC45A2	ENST00000510600.1	c.462A>G	p.Thr154Thr	synonymous_variant	Exon 3 of 5	3		ENSP00000424010.1

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142725 AN: 152138 Hom.: 67483 Cov.: 32

Gnomad AFR AF: 0.896

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.916

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.925

GnomAD2 exomes AF: 0.899 AC: 225960 AN: 251236 AF XY: 0.889

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.841

Gnomad ASJ exome AF: 0.982

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.996

Gnomad NFE exome AF: 0.989

Gnomad OTH exome AF: 0.931

GnomAD4 exome AF: 0.953 AC: 1393719 AN: 1461736 Hom.: 672762 Cov.: 67 AF XY: 0.943 AC XY: 685779 AN XY: 727164

African (AFR) AF: 0.890 AC: 29794 AN: 33472

American (AMR) AF: 0.853 AC: 38078 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 25653 AN: 26134

East Asian (EAS) AF: 0.773 AC: 30680 AN: 39696

South Asian (SAS) AF: 0.591 AC: 50961 AN: 86244

European-Finnish (FIN) AF: 0.997 AC: 53228 AN: 53408

Middle Eastern (MID) AF: 0.811 AC: 4674 AN: 5766

European-Non Finnish (NFE) AF: 0.993 AC: 1104029 AN: 1111962

Other (OTH) AF: 0.938 AC: 56622 AN: 60394

GnomAD4 genome AF: 0.938 AC: 142831 AN: 152256 Hom.: 67524 Cov.: 32 AF XY: 0.931 AC XY: 69316 AN XY: 74438

African (AFR) AF: 0.895 AC: 37180 AN: 41536

American (AMR) AF: 0.916 AC: 14012 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3406 AN: 3470

East Asian (EAS) AF: 0.811 AC: 4192 AN: 5168

South Asian (SAS) AF: 0.599 AC: 2882 AN: 4812

European-Finnish (FIN) AF: 0.997 AC: 10601 AN: 10628

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67437 AN: 68028

Other (OTH) AF: 0.923 AC: 1953 AN: 2116

Alfa AF: 0.970 Hom.: 311743

Bravo AF: 0.936

TwinsUK AF: 0.993 AC: 3681

ALSPAC AF: 0.993 AC: 3826

ESP6500AA AF: 0.899 AC: 3960

ESP6500EA AF: 0.990 AC: 8516

ExAC AF: 0.896 AC: 108827

Asia WGS AF: 0.683 AC: 2378 AN: 3478

EpiCase AF: 0.986

EpiControl AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Dec 16, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oculocutaneous albinism type 4 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oculocutaneous albinism type 4;C2673584:SKIN/HAIR/EYE PIGMENTATION 5, BLACK/NONBLACK HAIR Benign:1

Sep 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.22
DANN	Benign	0.69
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-0.94	T
PhyloP100		-2.4
PROVEAN	Benign	0.060	N
REVEL	Benign	0.067
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.49	T
Vest4		0.10
ClinPred		0.013	T
GERP RS		-9.5
Mutation Taster		=95/5	polymorphism (auto)

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: rs2287949; hg19: chr5-33954511; COSMIC: COSV56873781;