X-11298627-C-A

Variant names:

• chrX-11298627-C-A
• rs148259441
• NM_001142.2:c.224C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142.2(AMELX):​c.224C>A​(p.Pro75Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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: 0.0780

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22803235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMELX	NM_001142.2	c.224C>A	p.Pro75Gln	missense_variant	Exon 5 of 6	ENST00000380714.7	NP_001133.1
ARHGAP6	NM_013427.3	c.589-43920G>T		intron_variant	Intron 1 of 12	ENST00000337414.9	NP_038286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMELX	ENST00000380714.7	c.224C>A	p.Pro75Gln	missense_variant	Exon 5 of 6	1	NM_001142.2	ENSP00000370090.3
ARHGAP6	ENST00000337414.9	c.589-43920G>T		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Uncertain	0.61	.;D;.
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.89	.;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0060	B;B;B
Vest4		0.32
MVP		1.0
MPC		0.21
ClinPred		0.068	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148259441; hg19: chrX-11316747; COSMIC: COSV61636382;