15-48134287-A-G

Variant names:

• chr15-48134287-A-G
• rs1426654
• NM_205850.3:c.331A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_205850.3(SLC24A5):​c.331A>G​(p.Thr111Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,472 control chromosomes in the GnomAD database, including 59,639 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (17328 hom., cov: 32)
  • Exomes 𝑓: 0.081 (42311 hom.)
• Consequence: SLC24A5 NM_205850.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.57
• Publications: 224 publications found

Genes affected

SLC24A5 (HGNC:20611): (solute carrier family 24 member 5) This gene is a member of the potassium-dependent sodium/calcium exchanger family and encodes an intracellular membrane protein with 2 large hydrophilic loops and 2 sets of multiple transmembrane-spanning segments. Sequence variation in this gene has been associated with differences in skin pigmentation. [provided by RefSeq, Jul 2008]

SLC24A5 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. 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 1 benign, 5 uncertain in NM_205850.3
• BP4: Computational evidence support a benign effect (MetaRNN=1.1562395E-6).
• BP6: Variant 15-48134287-A-G is Benign according to our data. Variant chr15-48134287-A-G is described in ClinVar as Benign. ClinVar VariationId is 263273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC24A5	NM_205850.3	MANE Select	c.331A>G	p.Thr111Ala	missense	Exon 3 of 9	NP_995322.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC24A5	ENST00000341459.8	TSL:1 MANE Select	c.331A>G	p.Thr111Ala	missense	Exon 3 of 9	ENSP00000341550.3
	SLC24A5	ENST00000449382.2	TSL:1	c.151A>G	p.Thr51Ala	missense	Exon 2 of 8	ENSP00000389966.2
	SLC24A5	ENST00000463289.1	TSL:3	n.91A>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45263 AN: 152008 Hom.: 17249 Cov.: 32

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.230 AC: 57776 AN: 251246 AF XY: 0.196

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.521

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.993

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00347

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.0806 AC: 117787 AN: 1461346 Hom.: 42311 Cov.: 31 AF XY: 0.0786 AC XY: 57143 AN XY: 726986

African (AFR) AF: 0.829 AC: 27709 AN: 33414

American (AMR) AF: 0.499 AC: 22304 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26116

East Asian (EAS) AF: 0.994 AC: 39449 AN: 39686

South Asian (SAS) AF: 0.194 AC: 16730 AN: 86220

European-Finnish (FIN) AF: 0.0114 AC: 608 AN: 53418

Middle Eastern (MID) AF: 0.0337 AC: 194 AN: 5764

European-Non Finnish (NFE) AF: 0.00204 AC: 2272 AN: 1111664

Other (OTH) AF: 0.139 AC: 8421 AN: 60366

GnomAD4 genome AF: 0.299 AC: 45411 AN: 152126 Hom.: 17328 Cov.: 32 AF XY: 0.301 AC XY: 22390 AN XY: 74392

African (AFR) AF: 0.799 AC: 33131 AN: 41466

American (AMR) AF: 0.332 AC: 5068 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.985 AC: 5100 AN: 5180

South Asian (SAS) AF: 0.248 AC: 1197 AN: 4818

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00379 AC: 258 AN: 68002

Other (OTH) AF: 0.242 AC: 511 AN: 2108

Alfa AF: 0.129 Hom.: 21559

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.771 AC: 3388

ESP6500EA AF: 0.00489 AC: 42

ExAC AF: 0.228 AC: 27720

Asia WGS AF: 0.694 AC: 2411 AN: 3478

EpiCase AF: 0.00355

EpiControl AF: 0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17999355, 18650849, 24244186, 23071798, 16357253, 29025994, 31315583)

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.027
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.54
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-3.6	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.089
MPC		0.065
ClinPred		0.0071	T
GERP RS		5.5
Varity_R		0.077
gMVP		0.50
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1426654; hg19: chr15-48426484; COSMIC: COSV58316055; COSMIC: COSV58316055;