Genetic Variant ARX:p.Thr221Thr (chrX-25013332-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_139058.3(ARX):c.663C>T(p.Thr221Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 1,150,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T221T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000026 ( 0 hom. 6 hem. )

Consequence

ARX
NM_139058.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0200

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant X-25013332-G-A is Benign according to our data. Variant chrX-25013332-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 386858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.02 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.663C>T	p.Thr221Thr	synonymous_variant	Exon 2 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.663C>T	p.Thr221Thr	synonymous_variant	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

110346

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000491

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:

0.0000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000533

AC:

AN:

93801

AF XY:

0.0000609

show subpopulations

Gnomad AFR exome

AF:

0.000729

Gnomad AMR exome

AF:

0.0000527

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000260

AC:

AN:

1039838

Hom.:

Cov.:

AF XY:

0.0000177

AC XY:

AN XY:

339242

show subpopulations

Gnomad4 AFR exome

AF:

0.000203

AC:

AN:

24670

Gnomad4 AMR exome

AF:

0.0000360

AC:

AN:

27796

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

18545

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

26883

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

49496

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

26349

Gnomad4 NFE exome

AF:

0.0000244

AC:

AN:

818416

Gnomad4 Remaining exome

AF:

0.0000227

AC:

AN:

44138

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000145

AC:

AN:

110346

Hom.:

Cov.:

AF XY:

0.0000610

AC XY:

AN XY:

32780

show subpopulations

Gnomad4 AFR

AF:

0.000491

AC:

0.000490886

AN:

0.000490886

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000191

AC:

0.0000191018

AN:

0.0000191018

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00

Hom.:

Bravo

AF:

0.000136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Sep 14, 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

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.9

DANN

Benign

0.94

Mutation Taster

=100/0

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over