chr5-33963765-C-T

Variant names:

• chr5-33963765-C-T
• rs26722
• NM_016180.5:c.814G>A

Variant summary

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

The NM_016180.5(SLC45A2):​c.814G>A​(p.Glu272Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 1,614,096 control chromosomes in the GnomAD database, including 8,984 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (1099 hom., cov: 32)
  • Exomes 𝑓: 0.048 (7885 hom.)
• Consequence: SLC45A2 NM_016180.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.05
• Publications: 71 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=0.002914399).
• BP6: Variant 5-33963765-C-T is Benign according to our data. Variant chr5-33963765-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC45A2	NM_016180.5	c.814G>A	p.Glu272Lys	missense_variant	Exon 3 of 7	ENST00000296589.9	NP_057264.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000296589.9	c.814G>A	p.Glu272Lys	missense_variant	Exon 3 of 7	1	NM_016180.5	ENSP00000296589.4

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10049 AN: 152112 Hom.: 1093 Cov.: 32

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0944

GnomAD2 exomes AF: 0.118 AC: 29634 AN: 251350 AF XY: 0.113

Gnomad AFR exome AF: 0.0489

Gnomad AMR exome AF: 0.347

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.398

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.0484 AC: 70748 AN: 1461866 Hom.: 7885 Cov.: 34 AF XY: 0.0521 AC XY: 37888 AN XY: 727236

African (AFR) AF: 0.0484 AC: 1622 AN: 33480

American (AMR) AF: 0.335 AC: 14960 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 869 AN: 26136

East Asian (EAS) AF: 0.363 AC: 14399 AN: 39700

South Asian (SAS) AF: 0.197 AC: 16992 AN: 86258

European-Finnish (FIN) AF: 0.0130 AC: 697 AN: 53414

Middle Eastern (MID) AF: 0.173 AC: 999 AN: 5768

European-Non Finnish (NFE) AF: 0.0145 AC: 16100 AN: 1111996

Other (OTH) AF: 0.0681 AC: 4110 AN: 60392

GnomAD4 genome AF: 0.0661 AC: 10065 AN: 152230 Hom.: 1099 Cov.: 32 AF XY: 0.0730 AC XY: 5433 AN XY: 74430

African (AFR) AF: 0.0468 AC: 1945 AN: 41540

American (AMR) AF: 0.229 AC: 3509 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3472

East Asian (EAS) AF: 0.383 AC: 1978 AN: 5170

South Asian (SAS) AF: 0.194 AC: 932 AN: 4814

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10612

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0178 AC: 1209 AN: 68014

Other (OTH) AF: 0.0944 AC: 199 AN: 2108

Alfa AF: 0.0473 Hom.: 2133

Bravo AF: 0.0842

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.0497 AC: 219

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.107 AC: 12945

Asia WGS AF: 0.220 AC: 762 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0262

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15714523, 23071798, 22071478) -

Oculocutaneous albinism type 4 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

SLC45A2-related disorder Benign:1

Sep 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

SKIN/HAIR/EYE PIGMENTATION 5, BLACK/NONBLACK HAIR Other:1

Feb 13, 2018

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;.
PhyloP100		2.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.13
MPC		0.041
ClinPred		0.0047	T
GERP RS		2.1
Varity_R		0.037
gMVP		0.39
Mutation Taster		=100/0	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: rs26722; hg19: chr5-33963870; COSMIC: COSV99672368;