X-25013541-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_139058.3(ARX):c.454G>C(p.Ala152Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000956 in 104,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A152T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000096 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

ARX
NM_139058.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.299

Publications

0 publications found

Variant links:

Genes affected

ARX (HGNC:18060): (aristaless related homeobox) This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is thought to be involved in CNS development. Expansion of a polyalanine tract and other mutations in this gene cause X-linked cognitive disability and epilepsy. [provided by RefSeq, Jul 2016]

ARX Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
intellectual disability, X-linked, with or without seizures, ARX-related
Inheritance: XL Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
Partington syndrome
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked lissencephaly with abnormal genitalia
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
corpus callosum agenesis-abnormal genitalia syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
infantile epileptic-dyskinetic encephalopathy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked spasticity-intellectual disability-epilepsy syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ARX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27202952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.454G>C	p.Ala152Pro	missense_variant	Exon 2 of 5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5 link	c.454G>C	p.Ala152Pro	missense_variant	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes

AF:

0.00000956

AC:

AN:

104636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000976

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

694232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

210974

African (AFR)

AF:

0.00

AC:

AN:

13352

American (AMR)

AF:

0.00

AC:

AN:

2155

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5208

East Asian (EAS)

AF:

0.00

AC:

AN:

5459

South Asian (SAS)

AF:

0.00

AC:

AN:

15137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4704

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

622856

Other (OTH)

AF:

0.00

AC:

AN:

24049

GnomAD4 genome

AF:

0.00000956

AC:

AN:

104627

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29995

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29663

American (AMR)

AF:

0.0000975

AC:

AN:

10256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2552

East Asian (EAS)

AF:

0.00

AC:

AN:

3234

South Asian (SAS)

AF:

0.00

AC:

AN:

2481

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

195

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

50225

Other (OTH)

AF:

0.00

AC:

AN:

1434

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.0

PhyloP100

0.30

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.12

REVEL

Benign

0.20

Sift

Benign

0.17

Sift4G

Benign

0.24

Polyphen

0.0040

Vest4

0.32

MutPred

0.46

Gain of glycosylation at A152 (P = 0.0045);

MVP

0.79

MPC

1.4

ClinPred

0.051

GERP RS

1.5

Varity_R

0.17

gMVP

0.62

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over