Genetic Variant SLC24A4:p.Arg339Gly (chr14-92454034-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_153646.4(SLC24A4):c.1015C>G(p.Arg339Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC24A4
NM_153646.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.26

Publications

2 publications found

Variant links:

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]

SLC24A4 Gene-Disease associations (from GenCC):

amelogenesis imperfecta hypomaturation type 2A5
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
amelogenesis imperfecta, type 3A
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
amelogenesis imperfecta type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC24A4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC24A4	NM_153646.4 link	c.1015C>G	p.Arg339Gly	missense_variant	Exon 11 of 17	ENST00000532405.6	NP_705932.2	Q8NFF2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC24A4	ENST00000532405.6 link	c.1015C>G	p.Arg339Gly	missense_variant	Exon 11 of 17	1	NM_153646.4	ENSP00000431840.1		Q8NFF2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460760

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

85976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111504

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.085

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.9

.;.;M

PhyloP100

3.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.057

T;D;D

Polyphen

0.83

P;P;D

Vest4

0.86

MutPred

0.45

.;.;Gain of catalytic residue at G335 (P = 5e-04);

MVP

0.87

MPC

0.73

ClinPred

0.99

GERP RS

4.4

Varity_R

0.71

gMVP

0.86

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over