X-25007171-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_139058.3(ARX):c.1388G>A(p.Ser463Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,195,963 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S463S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

ARX
NM_139058.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.31

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41869292).

BP6

Variant X-25007171-C-T is Benign according to our data. Variant chrX-25007171-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540218.

BS2

High AC in GnomAdExome4 at 12 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.1388G>A	p.Ser463Asn	missense_variant	Exon 4 of 5	ENST00000379044.5	NP_620689.1	Q96QS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5 link	c.1388G>A	p.Ser463Asn	missense_variant	Exon 4 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3
ARX	ENST00000637993.1 link	c.-2G>A		5_prime_UTR_variant	Exon 1 of 2	5		ENSP00000490122.1		A0A1B0GUI3

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

147217

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1084537

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

353375

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25817

American (AMR)

AF:

0.00

AC:

AN:

34346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19121

East Asian (EAS)

AF:

0.00

AC:

AN:

29387

South Asian (SAS)

AF:

0.0000385

AC:

AN:

51962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.0000120

AC:

AN:

836146

Other (OTH)

AF:

0.00

AC:

AN:

45562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111426

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30632

American (AMR)

AF:

0.00

AC:

AN:

10667

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3500

South Asian (SAS)

AF:

0.00

AC:

AN:

2626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52954

Other (OTH)

AF:

0.00

AC:

AN:

1497

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ARX: PM2, PP3 -

Intellectual disability, X-linked, with or without seizures, ARX-related;C3463992:Developmental and epileptic encephalopathy, 1

Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.42

MetaSVM

Uncertain

0.079

MutationAssessor

Benign

0.55

PhyloP100

4.3

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.35

Sift

Benign

0.036

Sift4G

Benign

0.10

Polyphen

0.65

Vest4

0.43

MVP

0.93

MPC

2.2

ClinPred

0.56

GERP RS

4.2

PromoterAI

0.035

Neutral

(source)

Varity_R

0.55

gMVP

0.40

Mutation Taster

=91/9

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over