20-19681904-G-T

Position:

• chr20-19681904-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020689.4(SLC24A3):​c.814G>T​(p.Ala272Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC24A3 NM_020689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.991

Genes affected

SLC24A3 (HGNC:10977): (solute carrier family 24 member 3) Plasma membrane sodium/calcium exchangers are an important component of intracellular calcium homeostasis and electrical conduction. Potassium-dependent sodium/calcium exchangers such as SLC24A3 are believed to transport 1 intracellular calcium and 1 potassium ion in exchange for 4 extracellular sodium ions (Kraev et al., 2001 [PubMed 11294880]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08064741).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC24A3	NM_020689.4	c.814G>T	p.Ala272Ser	missense_variant	10/17	ENST00000328041.11	NP_065740.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC24A3	ENST00000328041.11	c.814G>T	p.Ala272Ser	missense_variant	10/17	1	NM_020689.4	ENSP00000333519.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

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 Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.814G>T (p.A272S) alteration is located in exon 10 (coding exon 10) of the SLC24A3 gene. This alteration results from a G to T substitution at nucleotide position 814, causing the alanine (A) at amino acid position 272 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.060	N;.
REVEL	Benign	0.031
Sift	Benign	0.78	T;.
Sift4G	Benign	0.66	T;T
Polyphen		0.0020	B;B
Vest4		0.080
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.28
MPC		0.45
ClinPred		0.13	T
GERP RS		3.1
Varity_R		0.038
gMVP		0.38

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: rs1204092994; hg19: chr20-19662548;