X-11298683-G-C

Variant names:

• chrX-11298683-G-C
• rs373800800
• NM_001142.2:c.280G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142.2(AMELX):​c.280G>C​(p.Val94Leu) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V94M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 21)
• Consequence: AMELX NM_001142.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.793
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13544169).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMELX	NM_001142.2	MANE Select	c.280G>C	p.Val94Leu	missense	Exon 5 of 6	NP_001133.1
	ARHGAP6	NM_013427.3	MANE Select	c.589-43976C>G		intron	N/A	NP_038286.2
	AMELX	NM_182680.1		c.322G>C	p.Val108Leu	missense	Exon 6 of 7	NP_872621.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMELX	ENST00000380714.7	TSL:1 MANE Select	c.280G>C	p.Val94Leu	missense	Exon 5 of 6	ENSP00000370090.3
	AMELX	ENST00000380712.7	TSL:1	c.322G>C	p.Val108Leu	missense	Exon 6 of 7	ENSP00000370088.3
	ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-43976C>G		intron	N/A	ENSP00000338967.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.79
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.15
Sift	Benign	0.62	T
Sift4G	Benign	0.84	T
Polyphen		0.010	B
Vest4		0.27
MutPred		0.45		Gain of glycosylation at P99 (P = 0.2014)
MVP		0.90
MPC		0.22
ClinPred		0.086	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.55
Mutation Taster		=98/2	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: rs373800800; hg19: chrX-11316803;