chr15-48134897-C-T

Position:

chr15-48134897-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_205850.3(SLC24A5):c.503C>T(p.Ser168Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000559 in 1,609,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S168T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SLC24A5
NM_205850.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.03

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]

SLC24A5 links:

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]

MYEF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A5	NM_205850.3 linkuse as main transcript	c.503C>T	p.Ser168Leu	missense_variant	5/9	ENST00000341459.8
MYEF2	NM_016132.5 linkuse as main transcript	c.*8011G>A		3_prime_UTR_variant	17/17	ENST00000324324.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A5	ENST00000341459.8 linkuse as main transcript	c.503C>T	p.Ser168Leu	missense_variant	5/9	1	NM_205850.3	P1	Q71RS6-1
SLC24A5	ENST00000449382.2 linkuse as main transcript	c.323C>T	p.Ser108Leu	missense_variant	4/8	1			Q71RS6-2
MYEF2	ENST00000324324.12 linkuse as main transcript	c.*8011G>A		3_prime_UTR_variant	17/17	1	NM_016132.5	P4
SLC24A5	ENST00000463289.1 linkuse as main transcript	n.263C>T		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250486

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000164

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457708

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724980

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 168 of the SLC24A5 protein (p.Ser168Leu). This variant is not present in population databases (gnomAD no frequency). 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: 1393352). 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 not expected to disrupt SLC24A5 protein function. 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

0.13

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.80

P;.

Vest4

0.47

MutPred

0.58

Loss of glycosylation at S165 (P = 0.1608);.;

MVP

0.81

MPC

0.24

ClinPred

0.98

GERP RS

5.6

Varity_R

0.58

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over