15-48121073-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_205850.3(SLC24A5):c.29C>T(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A10P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: SLC24A5 NM_205850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.834

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062205046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A5	NM_205850.3	c.29C>T	p.Ala10Val	missense_variant	1/9	ENST00000341459.8
SLC24A5	XM_047432394.1	c.29C>T	p.Ala10Val	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A5	ENST00000341459.8	c.29C>T	p.Ala10Val	missense_variant	1/9	1	NM_205850.3	P1
SLC24A5	ENST00000449382.2	c.29C>T	p.Ala10Val	missense_variant	1/8	1
SLC24A5	ENST00000482911.2	c.29C>T	p.Ala10Val	missense_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000838 AC: 21 AN: 250530 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135398

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461598 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 36 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74444

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000388 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 27, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the SLC24A5 protein (p.Ala10Val). This variant is present in population databases (rs189224179, gnomAD 0.04%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 20426782). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.062	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.078	T;D;D
Sift4G	Benign	0.068	T;D;D
Polyphen		0.0020	B;.;.
Vest4		0.092
MVP		0.62
MPC		0.066
ClinPred		0.039	T
GERP RS		3.6
Varity_R		0.029
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs189224179; hg19: chr15-48413270; COSMIC: COSV58316402; COSMIC: COSV58316402;