rs1426654

Positions:

• chr15-48134287-A-G
• chr15-48134287-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000341459.8(SLC24A5):​c.331A>G​(p.Thr111Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,472 control chromosomes in the GnomAD database, including 59,639 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (17328 hom., cov: 32)
  • Exomes 𝑓: 0.081 (42311 hom.)
• Consequence: SLC24A5 ENST00000341459.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1562395E-6).
• BP6: Variant 15-48134287-A-G is Benign according to our data. Variant chr15-48134287-A-G is described in ClinVar as [Benign]. Clinvar id is 263273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC24A5	NM_205850.3	c.331A>G	p.Thr111Ala	missense_variant	3/9	ENST00000341459.8	NP_995322.1
SLC24A5	XM_047432394.1	c.331A>G	p.Thr111Ala	missense_variant	3/8		XP_047288350.1
SLC24A5	XM_024449901.2	c.-9A>G		5_prime_UTR_variant	2/8		XP_024305669.2
SLC24A5	XM_047432395.1	c.-9A>G		5_prime_UTR_variant	3/9		XP_047288351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC24A5	ENST00000341459.8	c.331A>G	p.Thr111Ala	missense_variant	3/9	1	NM_205850.3	ENSP00000341550	P1
SLC24A5	ENST00000449382.2	c.151A>G	p.Thr51Ala	missense_variant	2/8	1		ENSP00000389966
SLC24A5	ENST00000463289.1	n.91A>G		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45263 AN: 152008 Hom.: 17249 Cov.: 32

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.230 AC: 57776 AN: 251246 Hom.: 21227 AF XY: 0.196 AC XY: 26657 AN XY: 135786

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.521

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.993

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00347

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.0806 AC: 117787 AN: 1461346 Hom.: 42311 Cov.: 31 AF XY: 0.0786 AC XY: 57143 AN XY: 726986

Gnomad4 AFR exome AF: 0.829

Gnomad4 AMR exome AF: 0.499

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.994

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.299 AC: 45411 AN: 152126 Hom.: 17328 Cov.: 32 AF XY: 0.301 AC XY: 22390 AN XY: 74392

Gnomad4 AFR AF: 0.799

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.00379

Gnomad4 OTH AF: 0.242

Alfa AF: 0.0780 Hom.: 10087

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.771 AC: 3388

ESP6500EA AF: 0.00489 AC: 42

ExAC AF: 0.228 AC: 27720

Asia WGS AF: 0.694 AC: 2411 AN: 3478

EpiCase AF: 0.00355

EpiControl AF: 0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	This variant is associated with the following publications: (PMID: 17999355, 18650849, 24244186, 23071798, 16357253, 29025994, 31315583) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.027
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.54
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.0000012	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-3.6	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	3.7	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.089
MPC		0.065
ClinPred		0.0071	T
GERP RS		5.5
Varity_R		0.077
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1426654; hg19: chr15-48426484; COSMIC: COSV58316055; COSMIC: COSV58316055;