X-25013554-T-G

Variant names:

• chrX-25013554-T-G
• rs797045301
• NM_139058.3:c.441A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_139058.3(ARX):​c.441A>C​(p.Ala147Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 758,632 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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. A147A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000069 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000030 (0 hom. 5 hem.)
• Consequence: ARX NM_139058.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.06
• Publications: 0 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-25013554-T-G is Benign according to our data. Variant chrX-25013554-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 588540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.06 with no splicing effect.
• BS2: High AC in GnomAd4 at 7 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.441A>C	p.Ala147Ala	synonymous	Exon 2 of 5	NP_620689.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	ENST00000379044.5	TSL:1 MANE Select	c.441A>C	p.Ala147Ala	synonymous	Exon 2 of 5	ENSP00000368332.4

Frequencies

GnomAD3 genomes AF: 0.0000688 AC: 7 AN: 101791 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000304 AC: 20 AN: 656842 Hom.: 0 Cov.: 30 AF XY: 0.0000253 AC XY: 5 AN XY: 197812

African (AFR) AF: 0.000159 AC: 2 AN: 12590

American (AMR) AF: 0.00 AC: 0 AN: 1287

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4326

East Asian (EAS) AF: 0.00 AC: 0 AN: 3784

South Asian (SAS) AF: 0.000141 AC: 2 AN: 14211

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1171

European-Non Finnish (NFE) AF: 0.0000252 AC: 15 AN: 596176

Other (OTH) AF: 0.0000453 AC: 1 AN: 22055

GnomAD4 genome AF: 0.0000688 AC: 7 AN: 101790 Hom.: 0 Cov.: 22 AF XY: 0.0000347 AC XY: 1 AN XY: 28842

African (AFR) AF: 0.000139 AC: 4 AN: 28842

American (AMR) AF: 0.000200 AC: 2 AN: 10009

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2537

East Asian (EAS) AF: 0.00 AC: 0 AN: 2891

South Asian (SAS) AF: 0.000479 AC: 1 AN: 2086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 189

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49511

Other (OTH) AF: 0.00 AC: 0 AN: 1398

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARX: BP4, BP7, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Inborn genetic diseases Benign:1

Dec 12, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.9
DANN	Benign	0.19
PhyloP100		-2.1
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

Other links and lift over

dbSNP: rs797045301; hg19: chrX-25031671;