NM_139058.3:c.1347C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_139058.3(ARX):c.1347C>T(p.Gly449Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,159,130 control chromosomes in the GnomAD database, including 435 homozygotes. There are 9,696 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 22 hom., 666 hem., cov: 22)

Exomes 𝑓: 0.027 ( 413 hom. 9030 hem. )

Consequence

ARX
NM_139058.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant X-25007212-G-A is Benign according to our data. Variant chrX-25007212-G-A is described in ClinVar as [Benign]. Clinvar id is 96451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-25007212-G-A is described in Lovd as [Likely_benign]. Variant chrX-25007212-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.01 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.1347C>T	p.Gly449Gly	synonymous_variant	Exon 4 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.1347C>T	p.Gly449Gly	synonymous_variant	Exon 4 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3
ARX	ENST00000637993.1 link	c.-43C>T		upstream_gene_variant		5		ENSP00000490122.1		A0A1B0GUI3

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

2220

AN:

111347

Hom.:

Cov.:

AF XY:

0.0199

AC XY:

666

AN XY:

33549

show subpopulations

Gnomad AFR

AF:

0.00412

Gnomad AMI

AF:

0.00147

Gnomad AMR

AF:

0.0485

Gnomad ASJ

AF:

0.00831

Gnomad EAS

AF:

0.000571

Gnomad SAS

AF:

0.0177

Gnomad FIN

AF:

0.0442

Gnomad MID

AF:

0.00851

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.0206

GnomAD3 exomes

AF:

0.0468

AC:

4717

AN:

100699

Hom.:

181

AF XY:

0.0450

AC XY:

1262

AN XY:

28027

show subpopulations

Gnomad AFR exome

AF:

0.00593

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.00966

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0259

Gnomad FIN exome

AF:

0.0514

Gnomad NFE exome

AF:

0.0306

Gnomad OTH exome

AF:

0.0295

GnomAD4 exome

AF:

0.0265

AC:

27794

AN:

1047738

Hom.:

413

Cov.:

AF XY:

0.0269

AC XY:

9030

AN XY:

335178

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.110

Gnomad4 ASJ exome

AF:

0.00907

Gnomad4 EAS exome

AF:

0.000112

Gnomad4 SAS exome

AF:

0.0228

Gnomad4 FIN exome

AF:

0.0470

Gnomad4 NFE exome

AF:

0.0252

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0199

AC:

2220

AN:

111392

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

666

AN XY:

33604

show subpopulations

Gnomad4 AFR

AF:

0.00411

Gnomad4 AMR

AF:

0.0485

Gnomad4 ASJ

AF:

0.00831

Gnomad4 EAS

AF:

0.000573

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.0442

Gnomad4 NFE

AF:

0.0229

Gnomad4 OTH

AF:

0.0204

Alfa

AF:

0.0219

Hom.:

163

Bravo

AF:

0.0231

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 27, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 26, 2022

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 09, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Benign:1

Feb 03, 2025

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

-0.52

CADD

Benign

DANN

Uncertain

0.98

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