X-25013554-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_139058.3(ARX):​c.441A>G​(p.Ala147Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 758,636 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 51 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. A147A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00024 (0 hom. 46 hem.)
• Consequence: ARX NM_139058.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-25013554-T-C is Benign according to our data. Variant chrX-25013554-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210333.
• BP7: Synonymous conserved (PhyloP=-2.06 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000196 (20/101790) while in subpopulation EAS AF = 0.00173 (5/2892). AF 95% confidence interval is 0.000681. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 20 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>G	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>G	p.Ala147Ala	synonymous	Exon 2 of 5	ENSP00000368332.4

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 20 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: 0.00172

Gnomad SAS AF: 0.000477

Gnomad FIN AF: 0.000270

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000141

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000236 AC: 155 AN: 656846 Hom.: 0 Cov.: 30 AF XY: 0.000233 AC XY: 46 AN XY: 197816

African (AFR) AF: 0.000159 AC: 2 AN: 12592

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4327

East Asian (EAS) AF: 0.000528 AC: 2 AN: 3785

South Asian (SAS) AF: 0.000563 AC: 8 AN: 14210

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

Middle Eastern (MID) AF: 0.000854 AC: 1 AN: 1171

European-Non Finnish (NFE) AF: 0.000223 AC: 133 AN: 596176

Other (OTH) AF: 0.000408 AC: 9 AN: 22056

GnomAD4 genome AF: 0.000196 AC: 20 AN: 101790 Hom.: 0 Cov.: 22 AF XY: 0.000173 AC XY: 5 AN XY: 28842

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

American (AMR) AF: 0.000200 AC: 2 AN: 10008

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

East Asian (EAS) AF: 0.00173 AC: 5 AN: 2892

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

European-Finnish (FIN) AF: 0.000270 AC: 1 AN: 3708

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

European-Non Finnish (NFE) AF: 0.000141 AC: 7 AN: 49511

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARX: BP4, BP7, BS2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Nov 10, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

History of neurodevelopmental disorder Benign:1

Oct 26, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Synonymous alterations with insufficient evidence to classify as benign

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.1
DANN	Benign	0.15
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; COSMIC: COSV108230120; COSMIC: COSV108230120;