rs587783201

Variant names:

• chrX-25013541-C-G
• rs587783201
• NM_139058.3:c.454G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-25013541-C-G
• chrX-25013541-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_139058.3(ARX):​c.454G>C​(p.Ala152Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000956 in 104,627 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A152T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.299
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27202952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.454G>C	p.Ala152Pro	missense_variant	Exon 2 of 5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.454G>C	p.Ala152Pro	missense_variant	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes AF: 0.00000956 AC: 1 AN: 104636 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000976

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 694232 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 210974

African (AFR) AF: 0.00 AC: 0 AN: 13352

American (AMR) AF: 0.00 AC: 0 AN: 2155

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5208

East Asian (EAS) AF: 0.00 AC: 0 AN: 5459

South Asian (SAS) AF: 0.00 AC: 0 AN: 15137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 622856

Other (OTH) AF: 0.00 AC: 0 AN: 24049

GnomAD4 genome AF: 0.00000956 AC: 1 AN: 104627 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 29995

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29663

American (AMR) AF: 0.0000975 AC: 1 AN: 10256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2552

East Asian (EAS) AF: 0.00 AC: 0 AN: 3234

South Asian (SAS) AF: 0.00 AC: 0 AN: 2481

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 195

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50225

Other (OTH) AF: 0.00 AC: 0 AN: 1434

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.64
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.30
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.20
Sift	Benign	0.17	T
Sift4G	Benign	0.24	T
Polyphen		0.0040	B
Vest4		0.32
MutPred		0.46		Gain of glycosylation at A152 (P = 0.0045);
MVP		0.79
MPC		1.4
ClinPred		0.051	T
GERP RS		1.5
Varity_R		0.17
gMVP		0.62
Mutation Taster		=87/13	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: rs587783201; hg19: chrX-25031658;