X-25015820-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_139058.3(ARX):c.-83C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 986,350 control chromosomes in the GnomAD database, including 9 homozygotes. There are 682 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 43 hem., cov: 24)

Exomes 𝑓: 0.0025 ( 9 hom. 639 hem. )

Consequence

ARX
NM_139058.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.874

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant X-25015820-G-T is Benign according to our data. Variant chrX-25015820-G-T is described in ClinVar as Benign. ClinVar VariationId is 446864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00163 (184/112801) while in subpopulation NFE AF = 0.0019 (101/53280). AF 95% confidence interval is 0.0016. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 184 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	NM_139058.3	MANE Select	c.-83C>A		5_prime_UTR	Exon 1 of 5	NP_620689.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ARX	ENST00000379044.5	TSL:1 MANE Select	c.-83C>A	5_prime_UTR	Exon 1 of 5	ENSP00000368332.4
ARX	ENST00000636609.1	TSL:5	n.36-175C>A	intron	N/A
ARX	ENST00000637394.1	TSL:5	n.68-175C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

185

AN:

112747

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000835

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00221

Gnomad FIN

AF:

0.000160

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00132

GnomAD4 exome

AF:

0.00246

AC:

2147

AN:

873549

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

639

AN XY:

231891

show subpopulations

African (AFR)

AF:

0.000327

AC:

AN:

21395

American (AMR)

AF:

0.000576

AC:

AN:

27798

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

361

AN:

17482

East Asian (EAS)

AF:

0.00

AC:

AN:

26393

South Asian (SAS)

AF:

0.00354

AC:

162

AN:

45765

European-Finnish (FIN)

AF:

0.000319

AC:

AN:

37571

Middle Eastern (MID)

AF:

0.000621

AC:

AN:

3219

European-Non Finnish (NFE)

AF:

0.00222

AC:

1454

AN:

655501

Other (OTH)

AF:

0.00346

AC:

133

AN:

38425

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00163

AC:

184

AN:

112801

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

34955

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

31086

American (AMR)

AF:

0.000834

AC:

AN:

10796

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00185

AC:

AN:

2709

European-Finnish (FIN)

AF:

0.000160

AC:

AN:

6262

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00190

AC:

101

AN:

53280

Other (OTH)

AF:

0.00131

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000920

Hom.:

Bravo

AF:

0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 24, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.87

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=299/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over