X-11298243-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001142.2(AMELX):c.110C>T(p.Thr37Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: AMELX NM_001142.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.71

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant X-11298243-C-T is Pathogenic according to our data. Variant chrX-11298243-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11140.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMELX	NM_001142.2	c.110C>T	p.Thr37Ile	missense_variant	4/6	ENST00000380714.7
ARHGAP6	NM_013427.3	c.589-43536G>A		intron_variant		ENST00000337414.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMELX	ENST00000380714.7	c.110C>T	p.Thr37Ile	missense_variant	4/6	1	NM_001142.2	P1
ARHGAP6	ENST00000337414.9	c.589-43536G>A		intron_variant		1	NM_013427.3	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097727 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363123

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amelogenesis imperfecta type 1E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2002

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;T;D
Sift4G	Benign	0.072	T;D;T
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.69		.;Loss of sheet (P = 0.0357);.;
MVP		0.99
MPC		0.88
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.17
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894733; hg19: chrX-11316363;