chr15-48134940-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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

Scores

9
8
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 0.226
Variant links:
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]

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ACMG classification

Classification made for transcript

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: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr15-48134940-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC24A5NM_205850.3 linkuse as main transcriptc.546T>A p.Ser182Arg missense_variant 5/9 ENST00000341459.8
MYEF2NM_016132.5 linkuse as main transcriptc.*7968A>T 3_prime_UTR_variant 17/17 ENST00000324324.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC24A5ENST00000341459.8 linkuse as main transcriptc.546T>A p.Ser182Arg missense_variant 5/91 NM_205850.3 P1Q71RS6-1
SLC24A5ENST00000449382.2 linkuse as main transcriptc.366T>A p.Ser122Arg missense_variant 4/81 Q71RS6-2
MYEF2ENST00000324324.12 linkuse as main transcriptc.*7968A>T 3_prime_UTR_variant 17/171 NM_016132.5 P4
SLC24A5ENST00000463289.1 linkuse as main transcriptn.306T>A non_coding_transcript_exon_variant 4/53

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 07, 2023This 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 submitterclinical testingGeneDxMay 10, 2016The 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024SLC24A5: 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057517995; hg19: chr15-48427137; API