X-11298265-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001142.2(AMELX):c.132C>A(p.Ser44Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S44N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AMELX NM_001142.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMELX	NM_001142.2	c.132C>A	p.Ser44Arg	missense_variant	4/6	ENST00000380714.7
ARHGAP6	NM_013427.3	c.589-43558G>T		intron_variant		ENST00000337414.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMELX	ENST00000380714.7	c.132C>A	p.Ser44Arg	missense_variant	4/6	1	NM_001142.2	P1
ARHGAP6	ENST00000337414.9	c.589-43558G>T		intron_variant		1	NM_013427.3	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2 Other:1

not provided, no classification provided

literature only

Medical Biology Lab, Gaziantep University

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	1.0	D;D;D;D;D;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.057	T;T;D
Polyphen		0.53	P;B;D
Vest4		0.60
MutPred		0.54		.;Gain of solvent accessibility (P = 0.0367);.;
MVP		0.92
MPC		0.77
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.56
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs431825178; hg19: chrX-11316385;