chr14-92460608-G-T

Variant names:

• chr14-92460608-G-T
• rs10498633
• NM_153646.4:c.1255+4000G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153646.4(SLC24A4):​c.1255+4000G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,144 control chromosomes in the GnomAD database, including 2,875 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2875 hom., cov: 32)
• Consequence: SLC24A4 NM_153646.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.163
• Publications: 136 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC24A4	NM_153646.4	c.1255+4000G>T		intron_variant	Intron 12 of 16	ENST00000532405.6	NP_705932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC24A4	ENST00000532405.6	c.1255+4000G>T		intron_variant	Intron 12 of 16	1	NM_153646.4	ENSP00000431840.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28513 AN: 152026 Hom.: 2876 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.0935

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.188 AC: 28527 AN: 152144 Hom.: 2875 Cov.: 32 AF XY: 0.185 AC XY: 13765 AN XY: 74396

African (AFR) AF: 0.135 AC: 5606 AN: 41516

American (AMR) AF: 0.193 AC: 2955 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 743 AN: 3468

East Asian (EAS) AF: 0.0932 AC: 482 AN: 5174

South Asian (SAS) AF: 0.179 AC: 863 AN: 4820

European-Finnish (FIN) AF: 0.178 AC: 1888 AN: 10592

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15433 AN: 67980

Other (OTH) AF: 0.193 AC: 407 AN: 2108

Alfa AF: 0.206 Hom.: 10915

Bravo AF: 0.184

Asia WGS AF: 0.134 AC: 464 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.3
DANN	Benign	0.70
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10498633; hg19: chr14-92926952;