5-33954406-T-C

Variant summary

Our verdict is Benign. Variant got -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. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S221R) 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:4
• Conservation: PhyloP100: -2.36

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 (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 id is 197309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-33954406-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SLC45A2	NM_016180.5	c.987A>G	p.Thr329=	synonymous_variant	4/7	ENST00000296589.9
SLC45A2	NM_001297417.4	c.661A>G	p.Ser221Gly	missense_variant	3/4
SLC45A2	NM_001012509.4	c.987A>G	p.Thr329=	synonymous_variant	4/6
SLC45A2	XM_047417259.1	c.747A>G	p.Thr249=	synonymous_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC45A2	ENST00000509381.1	c.661A>G	p.Ser221Gly	missense_variant	3/4	1
SLC45A2	ENST00000296589.9	c.987A>G	p.Thr329=	synonymous_variant	4/7	1	NM_016180.5	P1
SLC45A2	ENST00000382102.7	c.987A>G	p.Thr329=	synonymous_variant	4/6	1
SLC45A2	ENST00000510600.1	c.462A>G	p.Thr154=	synonymous_variant	3/5	3

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

GnomAD3 exomes AF: 0.899 AC: 225960 AN: 251236 Hom.: 104069 AF XY: 0.889 AC XY: 120635 AN XY: 135758

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 SAS exome AF: 0.581

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

Gnomad4 AFR exome AF: 0.890

Gnomad4 AMR exome AF: 0.853

Gnomad4 ASJ exome AF: 0.982

Gnomad4 EAS exome AF: 0.773

Gnomad4 SAS exome AF: 0.591

Gnomad4 FIN exome AF: 0.997

Gnomad4 NFE exome AF: 0.993

Gnomad4 OTH exome AF: 0.938

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

Gnomad4 AFR AF: 0.895

Gnomad4 AMR AF: 0.916

Gnomad4 ASJ AF: 0.982

Gnomad4 EAS AF: 0.811

Gnomad4 SAS AF: 0.599

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.991

Gnomad4 OTH AF: 0.923

Alfa AF: 0.974 Hom.: 149172

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 16, 2014

- -

Oculocutaneous albinism type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Oculocutaneous albinism type 4;C2673584:Skin/hair/eye pigmentation, variation in, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Benign	0.060	N
REVEL	Benign	0.067
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.10
ClinPred		0.013	T
GERP RS		-9.5

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