NM_139058.3:c.1638C>T

Variant names:

• chrX-25004721-G-A
• rs781186330
• NM_139058.3:c.1638C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_139058.3(ARX):​c.1638C>T​(p.Leu546Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L546L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARX NM_139058.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.978
• 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: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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: Orphanet, G2P
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant X-25004721-G-A is Benign according to our data. Variant chrX-25004721-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2939954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.978 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	NM_139058.3	MANE Select	c.1638C>T	p.Leu546Leu	synonymous	Exon 5 of 5	NP_620689.1	Q96QS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	ENST00000379044.5	TSL:1 MANE Select	c.1638C>T	p.Leu546Leu	synonymous	Exon 5 of 5	ENSP00000368332.4	Q96QS3
	ARX	ENST00000636885.1	TSL:5	n.*139C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00 AC: 0 AN: 105575 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 Data not reliable, filtered out with message: AS_VQSR AF: 9.51e-7 AC: 1 AN: 1051139 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 1 AN XY: 343201

African (AFR) AF: 0.0000402 AC: 1 AN: 24873

American (AMR) AF: 0.00 AC: 0 AN: 27915

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18605

East Asian (EAS) AF: 0.00 AC: 0 AN: 27146

South Asian (SAS) AF: 0.00 AC: 0 AN: 49818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36047

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3345

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819131

Other (OTH) AF: 0.00 AC: 0 AN: 44259

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.9
DANN	Benign	0.93
PhyloP100		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

Other links and lift over

dbSNP: rs781186330; hg19: chrX-25022838;