X-11298276-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001142.2(AMELX):​c.143C>T​(p.Pro48Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,207,719 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 23)
Exomes 𝑓: 0.000013 ( 0 hom. 3 hem. )

Consequence

AMELX
NM_001142.2 missense, splice_region

Scores

1
9
7
Splicing: ADA: 0.02777
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AMELXNM_001142.2 linkc.143C>T p.Pro48Leu missense_variant, splice_region_variant Exon 4 of 6 ENST00000380714.7 NP_001133.1 Q99217-1
ARHGAP6NM_013427.3 linkc.589-43569G>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
AMELXENST00000380714.7 linkc.143C>T p.Pro48Leu missense_variant, splice_region_variant Exon 4 of 6 1 NM_001142.2 ENSP00000370090.3 Q99217-1
ARHGAP6ENST00000337414.9 linkc.589-43569G>A intron_variant Intron 1 of 12 1 NM_013427.3 ENSP00000338967.4 O43182-1

Frequencies

GnomAD3 genomes
AF:
0.0000448
AC:
5
AN:
111587
Hom.:
0
Cov.:
23
AF XY:
0.0000887
AC XY:
3
AN XY:
33807
show subpopulations
Gnomad AFR
AF:
0.000131
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000378
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000327
AC:
6
AN:
183416
Hom.:
0
AF XY:
0.0000295
AC XY:
2
AN XY:
67872
show subpopulations
Gnomad AFR exome
AF:
0.000228
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000144
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000128
AC:
14
AN:
1096132
Hom.:
0
Cov.:
31
AF XY:
0.00000830
AC XY:
3
AN XY:
361574
show subpopulations
Gnomad4 AFR exome
AF:
0.000152
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000595
Gnomad4 OTH exome
AF:
0.0000869
GnomAD4 genome
AF:
0.0000448
AC:
5
AN:
111587
Hom.:
0
Cov.:
23
AF XY:
0.0000887
AC XY:
3
AN XY:
33807
show subpopulations
Gnomad4 AFR
AF:
0.000131
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000378
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 23, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.185C>T (p.P62L) alteration is located in exon 5 (coding exon 4) of the AMELX gene. This alteration results from a C to T substitution at nucleotide position 185, causing the proline (P) at amino acid position 62 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
0.16
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.55
.;D;.
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Pathogenic
0.52
D
MetaRNN
Uncertain
0.45
T;T;T
MetaSVM
Uncertain
0.34
D
MutationAssessor
Uncertain
2.3
.;M;.
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.3
N;N;N
REVEL
Uncertain
0.47
Sift
Benign
0.11
T;T;T
Sift4G
Uncertain
0.048
D;T;D
Polyphen
0.0050
B;B;D
Vest4
0.55
MVP
0.98
MPC
0.77
ClinPred
0.054
T
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.090
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.028
dbscSNV1_RF
Benign
0.18
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs144955572; hg19: chrX-11316396; API