chrX-11294835-C-A

Variant names:

• chrX-11294835-C-A
• NM_001142.2:c.47C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001142.2(AMELX):​c.47C>A​(p.Ala16Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AMELX NM_001142.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.00
• Publications: 0 publications found

Genes affected

AMELX (HGNC:461): (amelogenin X-linked) This gene encodes a member of the amelogenin family of extracellular matrix proteins. Amelogenins are involved in biomineralization during tooth enamel development. Mutations in this gene cause X-linked amelogenesis imperfecta. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ARHGAP6 (HGNC:676): (Rho GTPase activating protein 6) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of actin polymerization at the plasma membrane during several cellular processes. This protein is thought to have two independent functions, one as a GTPase-activating protein with specificity for RhoA, and another as a cytoskeletal protein that promotes actin remodeling. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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, 0.833
• PP5: Variant X-11294835-C-A is Pathogenic according to our data. Variant chrX-11294835-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2445234.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142.2. 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
	AMELX	NM_001142.2	MANE Select	c.47C>A	p.Ala16Asp	missense	Exon 2 of 6	NP_001133.1	Q99217-1
	ARHGAP6	NM_013427.3	MANE Select	c.589-40128G>T		intron	N/A	NP_038286.2	O43182-1
	AMELX	NM_182680.1		c.47C>A	p.Ala16Asp	missense	Exon 2 of 7	NP_872621.1	Q99217-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMELX	ENST00000380714.7	TSL:1 MANE Select	c.47C>A	p.Ala16Asp	missense	Exon 2 of 6	ENSP00000370090.3	Q99217-1
	AMELX	ENST00000380712.7	TSL:1	c.47C>A	p.Ala16Asp	missense	Exon 2 of 7	ENSP00000370088.3	Q99217-3
	ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-40128G>T		intron	N/A	ENSP00000338967.4	O43182-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Amelogenesis imperfecta type 1E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.1	L
PhyloP100		4.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.025	D
Polyphen		0.53	P
Vest4		0.72
MutPred		0.29		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.97
MPC		1.0
ClinPred		0.82	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.61
Mutation Taster		=68/32	polymorphism

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

hg19: chrX-11312955;