rs587777537

Variant names:

• chr14-92442132-C-T
• rs587777537
• NM_153646.4:c.437C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_153646.4(SLC24A4):​c.437C>T​(p.Ala146Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC24A4 NM_153646.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.71
• Publications: 5 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 14-92442132-C-T is Pathogenic according to our data. Variant chr14-92442132-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 139659.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC24A4	NM_153646.4	c.437C>T	p.Ala146Val	missense_variant	Exon 5 of 17	ENST00000532405.6	NP_705932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC24A4	ENST00000532405.6	c.437C>T	p.Ala146Val	missense_variant	Exon 5 of 17	1	NM_153646.4	ENSP00000431840.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amelogenesis imperfecta hypomaturation type 2A5 Pathogenic:1

Mar 12, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.5	.;H;H;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.97
MutPred		0.77		.;Gain of catalytic residue at S149 (P = 0);Gain of catalytic residue at S149 (P = 0);.;
MVP		0.96
MPC		0.97
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777537; hg19: chr14-92908476;