Genetic Variant ARX:p.Gln548Leu (chrX-25004716-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139058.3(ARX):c.1643A>T(p.Gln548Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000883 in 113,199 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 25)

Consequence

ARX
NM_139058.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.1643A>T	p.Gln548Leu	missense_variant	Exon 5 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.1643A>T	p.Gln548Leu	missense_variant	Exon 5 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3
ARX	ENST00000636885.1 link	n.*144A>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000884

AC:

AN:

113151

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35327

show subpopulations

Gnomad AFR

AF:

0.0000320

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000883

AC:

AN:

113199

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35385

show subpopulations

Gnomad4 AFR

AF:

0.0000320

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1643A>T (p.Q548L) alteration is located in exon 5 (coding exon 5) of the ARX gene. This alteration results from a A to T substitution at nucleotide position 1643, causing the glutamine (Q) at amino acid position 548 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.72

Sift

Benign

0.050

Sift4G

Benign

1.0

Polyphen

0.98

Vest4

0.54

MutPred

0.46

Loss of disorder (P = 0.0595);

MVP

0.95

MPC

2.2

ClinPred

0.98

GERP RS

4.1

Varity_R

0.38

gMVP

0.63

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over