15-48121099-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_205850.3(SLC24A5):c.55C>A(p.Leu19Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SLC24A5 NM_205850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0100

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02415824).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000281 (41/1461620) while in subpopulation AFR AF= 0.000806 (27/33478). AF 95% confidence interval is 0.000569. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A5	NM_205850.3	c.55C>A	p.Leu19Met	missense_variant	1/9	ENST00000341459.8
SLC24A5	XM_047432394.1	c.55C>A	p.Leu19Met	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A5	ENST00000341459.8	c.55C>A	p.Leu19Met	missense_variant	1/9	1	NM_205850.3	P1
SLC24A5	ENST00000449382.2	c.55C>A	p.Leu19Met	missense_variant	1/8	1
SLC24A5	ENST00000482911.2	c.55C>A	p.Leu19Met	missense_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 250616 Hom.: 0 AF XY: 0.0000960 AC XY: 13 AN XY: 135452

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461620 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 727118

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74472

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000662 Hom.: 0

Bravo AF: 0.000340

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

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

Oct 28, 2022

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 19 of the SLC24A5 protein (p.Leu19Met). This variant is present in population databases (rs373895181, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SLC24A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1404751). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	11
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.024	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.060	T;D;D
Sift4G	Uncertain	0.060	T;T;T
Polyphen		0.23	B;.;.
Vest4		0.30
MVP		0.47
MPC		0.080
ClinPred		0.011	T
GERP RS		-0.031
Varity_R		0.058
gMVP		0.58

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: rs373895181; hg19: chr15-48413296;