rs769996976

Variant names:

• chrX-25015551-C-T
• rs769996976
• NM_139058.3:c.187G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_139058.3(ARX):​c.187G>A​(p.Ala63Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A63V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.69
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0959934).
• BP6: Variant X-25015551-C-T is Benign according to our data. Variant chrX-25015551-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 581240.

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.187G>A	p.Ala63Thr	missense	Exon 1 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.187G>A	p.Ala63Thr	missense	Exon 1 of 5	ENSP00000368332.4	Q96QS3
	ARX	ENST00000636609.1	TSL:5	n.*30G>A		downstream_gene	N/A
	ARX	ENST00000637394.1	TSL:5	n.*62G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00000885 AC: 1 AN: 113049 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000926

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

GnomAD2 exomes AF: 0.0000114 AC: 2 AN: 175835 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

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: 0.000229

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1096314 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361956

African (AFR) AF: 0.00 AC: 0 AN: 26370

American (AMR) AF: 0.0000570 AC: 2 AN: 35074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19297

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00 AC: 0 AN: 53548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4085

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841331

Other (OTH) AF: 0.0000217 AC: 1 AN: 46018

GnomAD4 genome AF: 0.00000885 AC: 1 AN: 113049 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35167

African (AFR) AF: 0.00 AC: 0 AN: 31169

American (AMR) AF: 0.0000926 AC: 1 AN: 10800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3595

South Asian (SAS) AF: 0.00 AC: 0 AN: 2737

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53400

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Corpus callosum agenesis-abnormal genitalia syndrome;C0796244:Intellectual disability, X-linked, with or without seizures, ARX-related;C0796250:Partington syndrome;C1846171:X-linked lissencephaly with abnormal genitalia;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	-	1	Intellectual disability, X-linked, with or without seizures, ARX-related;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.79	N
PhyloP100		1.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.26
Sift	Benign	0.55	T
Sift4G	Benign	0.50	T
Polyphen		0.0030	B
Vest4		0.066
MutPred		0.054		Gain of phosphorylation at A63 (P = 0.0208)
MVP		0.79
MPC		1.1
ClinPred		0.13	T
GERP RS		3.1
PromoterAI		0.0055	Neutral
Varity_R		0.16
gMVP		0.29
Mutation Taster		=97/3	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: rs769996976; hg19: chrX-25033668;