X-11298627-C-T

Position:

chrX-11298627-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001142.2(AMELX):c.224C>T(p.Pro75Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000877 in 1,208,321 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000082 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000088 ( 0 hom. 31 hem. )

Consequence

AMELX
NM_001142.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0780

Variant links:

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]

AMELX links:

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]

ARHGAP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1744031).

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMELX	NM_001142.2 link	c.224C>T	p.Pro75Leu	missense_variant	Exon 5 of 6	ENST00000380714.7	NP_001133.1	Q99217-1
ARHGAP6	NM_013427.3 link	c.589-43920G>A		intron_variant	Intron 1 of 12	ENST00000337414.9	NP_038286.2	O43182-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMELX	ENST00000380714.7 link	c.224C>T	p.Pro75Leu	missense_variant	Exon 5 of 6	1	NM_001142.2	ENSP00000370090.3		Q99217-1
ARHGAP6	ENST00000337414.9 link	c.589-43920G>A		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4		O43182-1

Frequencies

GnomAD3 genomes

AF:

0.0000817

AC:

AN:

110116

Hom.:

Cov.:

AF XY:

0.0000928

AC XY:

AN XY:

32330

show subpopulations

Gnomad AFR

AF:

0.000232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000600

AC:

AN:

183448

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

67880

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000610

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000883

AC:

AN:

1098205

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

363573

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000923

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000817

AC:

AN:

110116

Hom.:

Cov.:

AF XY:

0.0000928

AC XY:

AN XY:

32330

show subpopulations

Gnomad4 AFR

AF:

0.000232

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000379

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2024

The c.266C>T (p.P89L) alteration is located in exon 6 (coding exon 5) of the AMELX gene. This alteration results from a C to T substitution at nucleotide position 266, causing the proline (P) at amino acid position 89 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

.;D;.

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.76

T;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.6

.;L;.

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.068

T;T;T

Polyphen

0.14

B;B;B

Vest4

0.18

MVP

0.99

MPC

0.23

ClinPred

0.078

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over