14-92325945-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153646.4(SLC24A4):c.208G>A(p.Gly70Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000034 (0 hom.)
• Consequence: SLC24A4 NM_153646.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

Genes affected

SLC24A4 (HGNC:10978): (solute carrier family 24 member 4) This gene encodes a sodium/potassium/calcium exchange protein. The encoded antiporter transports one calcium and one potassium ion in exchange for four sodium ions and has been implicated in amelogenesis and enamel maturation. Certain variants in this gene have been associated with skin, hair, and eye pigmentation, while other variants have been identified in people with hypomaturation-type amelogenesis imperfecta. [provided by RefSeq, Nov 2023]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29866505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A4	NM_153646.4	c.208G>A	p.Gly70Arg	missense_variant	2/17	ENST00000532405.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A4	ENST00000532405.6	c.208G>A	p.Gly70Arg	missense_variant	2/17	1	NM_153646.4	A1
SLC24A4	ENST00000393265.6	c.16G>A	p.Gly6Arg	missense_variant	2/17	1
SLC24A4	ENST00000676001.1	c.208G>A	p.Gly70Arg	missense_variant	3/18			A1
SLC24A4	ENST00000531433.5	c.208G>A	p.Gly70Arg	missense_variant	3/18	2		P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460330 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726418

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.208G>A (p.G70R) alteration is located in exon 2 (coding exon 2) of the SLC24A4 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the glycine (G) at amino acid position 70 to be replaced by an arginine (R). 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	0.010	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.12
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.011	D;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.79, 0.0030	.;P;B
Vest4		0.56
MutPred		0.35		.;Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);
MVP		0.81
MPC		0.34
ClinPred		0.72	D
GERP RS		4.8
Varity_R		0.18
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr14-92792289;