NM_139058.3:c.91A>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_139058.3(ARX):c.91A>C(p.Ser31Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000579 in 1,208,250 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

ARX
NM_139058.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.04

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: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
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: Orphanet, G2P
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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
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 -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

BS2

High AC in GnomAdExome4 at 5 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139058.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	NM_139058.3	MANE Select	c.91A>C	p.Ser31Arg	missense	Exon 1 of 5	NP_620689.1	Q96QS3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARX	ENST00000379044.5	TSL:1 MANE Select	c.91A>C	p.Ser31Arg	missense	Exon 1 of 5	ENSP00000368332.4	Q96QS3
ARX	ENST00000636609.1	TSL:5	n.36-2A>C		splice_acceptor intron	N/A
ARX	ENST00000637394.1	TSL:5	n.68-2A>C		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112253

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1095997

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361591

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26371

American (AMR)

AF:

0.00

AC:

AN:

35058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19321

East Asian (EAS)

AF:

0.00

AC:

AN:

30174

South Asian (SAS)

AF:

0.00

AC:

AN:

53519

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40397

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000595

AC:

AN:

841009

Other (OTH)

AF:

0.00

AC:

AN:

46013

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000178

AC:

AN:

112253

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34409

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30940

American (AMR)

AF:

0.00

AC:

AN:

10742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53194

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.0

PhyloP100

7.0

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.79

MutPred

0.29

Gain of MoRF binding (P = 0.0087)

MVP

0.98

MPC

1.3

ClinPred

0.98

GERP RS

5.2

PromoterAI

0.062

Neutral

(source)

Varity_R

0.94

gMVP

0.79

Mutation Taster

=29/71

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over