20-19212849-C-A

Variant summary

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

The NM_020689.4(SLC24A3):c.7C>A(p.Pro3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 950,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. P3L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: SLC24A3 NM_020689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.146

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]

(HGNC:):

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=0.11027181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A3	NM_020689.4	c.7C>A	p.Pro3Thr	missense_variant	1/17	ENST00000328041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A3	ENST00000328041.11	c.7C>A	p.Pro3Thr	missense_variant	1/17	1	NM_020689.4	P1
	ENST00000446849.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 950758 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 446808

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Sep 14, 2023

The c.7C>A (p.P3T) alteration is located in exon 1 (coding exon 1) of the SLC24A3 gene. This alteration results from a C to A substitution at nucleotide position 7, causing the proline (P) at amino acid position 3 to be replaced by a threonine (T). 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	0.068
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.39	N
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.22	N;.
REVEL	Benign	0.023
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0090	B;B
Vest4		0.099
MutPred		0.32		Gain of phosphorylation at P3 (P = 0.0051);Gain of phosphorylation at P3 (P = 0.0051);
MVP		0.17
MPC		1.1
ClinPred		0.27	T
GERP RS		2.0
Varity_R		0.12
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-19193493;