15-48134940-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_205850.3(SLC24A5):c.546T>A(p.Ser182Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S182G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC24A5 NM_205850.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.226

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]

MYEF2 (HGNC:17940): (myelin expression factor 2) Enables RNA binding activity. Involved in myotube differentiation and neuron differentiation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=4 (size 20) in uniprot entity NCKX5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_205850.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 15-48134940-T-A is Pathogenic according to our data. Variant chr15-48134940-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372809.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr15-48134940-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A5	NM_205850.3	c.546T>A	p.Ser182Arg	missense_variant	5/9	ENST00000341459.8
MYEF2	NM_016132.5	c.*7968A>T		3_prime_UTR_variant	17/17	ENST00000324324.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A5	ENST00000341459.8	c.546T>A	p.Ser182Arg	missense_variant	5/9	1	NM_205850.3	P1
SLC24A5	ENST00000449382.2	c.366T>A	p.Ser122Arg	missense_variant	4/8	1
MYEF2	ENST00000324324.12	c.*7968A>T		3_prime_UTR_variant	17/17	1	NM_016132.5	P4
SLC24A5	ENST00000463289.1	n.306T>A		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 182 of the SLC24A5 protein (p.Ser182Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculocutaneous albinism type VI (PMID: 23985994, 29345414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372809). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC24A5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC24A5 function (PMID: 27129268, 32274888). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2016	The S182R variant in the SLC24A5 gene has been reported previously in the homozygous state in an individual of Syrian ancestry with oculocutaneous albinism (Morice-Picard et al., 2014). The S182R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S182R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The S182R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SLC24A5: PM2, PM3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.79		Gain of methylation at S182 (P = 0.0061);.;
MVP		0.81
MPC		0.42
ClinPred		1.0	D
GERP RS		-2.8
Varity_R		0.99
gMVP		0.98

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: rs1057517995; hg19: chr15-48427137;