rs4406992

Variant names:

• chr14-92470276-C-T
• rs4406992
• NM_153646.4:c.1256-12404C>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.1256-12404C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 152,038 control chromosomes in the GnomAD database, including 35,682 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 0.67 (35682 hom., cov: 31)
• Consequence: SLC24A4 NM_153646.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.755
• Publications: 7 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153646.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC24A4	NM_153646.4	MANE Select	c.1256-12404C>T		intron	N/A	NP_705932.2	Q8NFF2-1
	SLC24A4	NM_001378620.1		c.1256-12404C>T		intron	N/A	NP_001365549.1	Q8NFF2-1
	SLC24A4	NM_001425254.1		c.1199-12404C>T		intron	N/A	NP_001412183.1	Q8NFF2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC24A4	ENST00000532405.6	TSL:1 MANE Select	c.1256-12404C>T		intron	N/A	ENSP00000431840.1	Q8NFF2-1
	SLC24A4	ENST00000393265.6	TSL:1	c.1064-12404C>T		intron	N/A	ENSP00000376948.2	Q8NFF2-2
	SLC24A4	ENST00000525557.5	TSL:1	c.851-12404C>T		intron	N/A	ENSP00000432464.1	H0YCX3

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102453 AN: 151918 Hom.: 35660 Cov.: 31

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.757

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.695

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.684

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

GnomAD4 genome AF: 0.674 AC: 102521 AN: 152038 Hom.: 35682 Cov.: 31 AF XY: 0.677 AC XY: 50289 AN XY: 74320

African (AFR) AF: 0.494 AC: 20486 AN: 41430

American (AMR) AF: 0.702 AC: 10719 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 2628 AN: 3472

East Asian (EAS) AF: 0.582 AC: 3004 AN: 5162

South Asian (SAS) AF: 0.695 AC: 3346 AN: 4816

European-Finnish (FIN) AF: 0.773 AC: 8171 AN: 10568

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51912 AN: 67994

Other (OTH) AF: 0.685 AC: 1448 AN: 2114

Alfa AF: 0.740 Hom.: 21273

Bravo AF: 0.660

Asia WGS AF: 0.652 AC: 2268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.34
PhyloP100		-0.76
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4406992;

hg19: chr14-92936620;