chrX-11298932-G-A

Variant names:

• chrX-11298932-G-A
• rs104894734
• NM_001142.2:c.529G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142.2(AMELX):​c.529G>A​(p.Glu177Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AMELX NM_001142.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39
• Publications: 8 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

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.529G>A	p.Glu177Lys	missense	Exon 5 of 6	NP_001133.1	Q99217-1
	ARHGAP6	NM_013427.3	MANE Select	c.589-44225C>T		intron	N/A	NP_038286.2	O43182-1
	AMELX	NM_182680.1		c.571G>A	p.Glu191Lys	missense	Exon 6 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.529G>A	p.Glu177Lys	missense	Exon 5 of 6	ENSP00000370090.3	Q99217-1
	AMELX	ENST00000380712.7	TSL:1	c.571G>A	p.Glu191Lys	missense	Exon 6 of 7	ENSP00000370088.3	Q99217-3
	ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-44225C>T		intron	N/A	ENSP00000338967.4	O43182-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000550 AC: 1 AN: 181773 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.63		Gain of methylation at E177 (P = 0.0031)
MVP		0.90
MPC		0.25
ClinPred		0.81	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.67
Mutation Taster		=85/15	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

dbSNP: rs104894734; hg19: chrX-11317052;