NM_139058.3:c.216C>A

Variant names:

• chrX-25013779-G-T
• rs587783195
• NM_139058.3:c.216C>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.216C>A​(p.Ser72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000123 in 815,740 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. S72T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000012 (0 hom. 0 hem.)
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.155
• Publications: 1 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: 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=0.15576869).
• BP6: Variant X-25013779-G-T is Benign according to our data. Variant chrX-25013779-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157752.

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.216C>A	p.Ser72Arg	missense	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.216C>A	p.Ser72Arg	missense	Exon 2 of 5	ENSP00000368332.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000123 AC: 1 AN: 815740 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 249172

African (AFR) AF: 0.00 AC: 0 AN: 17667

American (AMR) AF: 0.00 AC: 0 AN: 6163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10255

East Asian (EAS) AF: 0.00 AC: 0 AN: 19977

South Asian (SAS) AF: 0.00 AC: 0 AN: 14098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2008

European-Non Finnish (NFE) AF: 0.00000143 AC: 1 AN: 696913

Other (OTH) AF: 0.00 AC: 0 AN: 33083

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.15
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Benign	0.044	D
Sift4G	Benign	0.54	T
Polyphen		0.091	B
Vest4		0.16
MutPred		0.28		Gain of solvent accessibility (P = 0.006)
MVP		0.77
MPC		1.3
ClinPred		0.087	T
GERP RS		2.8
Varity_R		0.18
gMVP		0.15
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587783195; hg19: chrX-25031896;