rs1556056580

Variant names:

• chrX-25013780-C-G
• rs1556056580
• NM_139058.3:c.215G>C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_139058.3(ARX):​c.215G>C​(p.Ser72Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 815,944 control chromosomes in the GnomAD database, including 1 homozygotes. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000022 (1 hom. 8 hem.)
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.358

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08672586).
• BP6: Variant X-25013780-C-G is Benign according to our data. Variant chrX-25013780-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540219.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000221 (18/815944) while in subpopulation AMR AF= 0.00276 (17/6149). AF 95% confidence interval is 0.00176. There are 1 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.215G>C	p.Ser72Thr	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.215G>C	p.Ser72Thr	missense_variant	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000221 AC: 18 AN: 815944 Hom.: 1 Cov.: 32 AF XY: 0.0000321 AC XY: 8 AN XY: 249268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00276

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

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215G>C (p.S72T) alteration is located in exon 2 (coding exon 2) of the ARX gene. This alteration results from a G to C substitution at nucleotide position 215, causing the serine (S) at amino acid position 72 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability, X-linked, with or without seizures, ARX-related;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.36	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.23
Sift	Benign	0.75	T
Sift4G	Benign	0.59	T
Polyphen		0.0030	B
Vest4		0.066
MutPred		0.13		Gain of glycosylation at S71 (P = 0.0588);
MVP		0.71
MPC		1.0
ClinPred		0.037	T
GERP RS		1.9
Varity_R		0.11
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556056580; hg19: chrX-25031897;