chrX-25013779-G-C

Variant names:

• chrX-25013779-G-C
• NM_139058.3:c.216C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139058.3(ARX):​c.216C>G​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: 0.155

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15726233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.216C>G	p.Ser72Arg	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.216C>G	p.Ser72Arg	missense_variant	Exon 2 of 5	1	NM_139058.3	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000143

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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	0.40	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.69	N
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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-25031896;