rs104894737

Variant names:

• chrX-11294790-T-C
• rs104894737
• NM_001142.2:c.2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001142.2(AMELX):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AMELX NM_001142.2 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.05
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 17 codons. Genomic position: 11294837. Lost 0.085 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-11294790-T-C is Pathogenic according to our data. Variant chrX-11294790-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11145.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2T>C	p.Met1?	start_lost	Exon 2 of 6	NP_001133.1
	ARHGAP6	NM_013427.3	MANE Select	c.589-40083A>G		intron	N/A	NP_038286.2
	AMELX	NM_182680.1		c.2T>C	p.Met1?	start_lost	Exon 2 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.2T>C	p.Met1?	start_lost	Exon 2 of 6	ENSP00000370090.3
	AMELX	ENST00000380712.7	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 7	ENSP00000370088.3
	ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-40083A>G		intron	N/A	ENSP00000338967.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Amelogenesis imperfecta type 1E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.28	T
PhyloP100		4.1
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.020	B
Vest4		0.86
MutPred		0.69		Gain of glycosylation at M1 (P = 0.0283)
MVP		0.90
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.87
gMVP		0.47
Mutation Taster		=12/188	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.11		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: rs104894737; hg19: chrX-11312910;