rs28935479

Variant names:

• chrX-25013139-C-T
• rs28935479
• NM_139058.3:c.856G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3 PP5 BS2

The NM_139058.3(ARX):​c.856G>A​(p.Gly286Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 1,086,741 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. G286D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000015 (0 hom. 6 hem.)
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 1.64
• Publications: 3 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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant X-25013139-C-T is Pathogenic according to our data. Variant chrX-25013139-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11199.
• BS2: High AC in GnomAdExome4 at 16 AD,XL gene.

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.856G>A	p.Gly286Ser	missense	Exon 2 of 5	NP_620689.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	ENST00000379044.5	TSL:1 MANE Select	c.856G>A	p.Gly286Ser	missense	Exon 2 of 5	ENSP00000368332.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000648 AC: 1 AN: 154354 AF XY: 0.0000203

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: 0.0000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 16 AN: 1086741 Hom.: 0 Cov.: 32 AF XY: 0.0000169 AC XY: 6 AN XY: 355309

African (AFR) AF: 0.00 AC: 0 AN: 26207

American (AMR) AF: 0.00 AC: 0 AN: 34372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19134

East Asian (EAS) AF: 0.00 AC: 0 AN: 29845

South Asian (SAS) AF: 0.00 AC: 0 AN: 52573

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38479

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3124

European-Non Finnish (NFE) AF: 0.0000191 AC: 16 AN: 837478

Other (OTH) AF: 0.00 AC: 0 AN: 45529

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	-	-	Intellectual disability, X-linked, with or without seizures, ARX-related (1)
-	1	-	Intellectual disability, X-linked, with or without seizures, ARX-related;C3463992:Developmental and epileptic encephalopathy, 1 (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.59
Sift	Benign	0.058	T
Sift4G	Benign	0.15	T
Polyphen		0.12	B
Vest4		0.67
MutPred		0.70		Gain of glycosylation at G286 (P = 0.0068)
MVP		0.97
MPC		2.3
ClinPred		0.38	T
GERP RS		2.9
Varity_R		0.29
gMVP		0.21
Mutation Taster		=95/5	disease causing (ClinVar)

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: rs28935479; hg19: chrX-25031256;