rs797045294

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_139058.3(ARX):​c.300G>A​(p.Ala100=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 888,972 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.000049 ( 0 hom. 16 hem. )

Consequence

ARX
NM_139058.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -3.50
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
Variant X-25013695-C-T is Benign according to our data. Variant chrX-25013695-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210324.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.
BP7
Synonymous conserved (PhyloP=-3.5 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000487 (38/779905) while in subpopulation SAS AF= 0.00246 (34/13842). AF 95% confidence interval is 0.00181. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARXNM_139058.3 linkuse as main transcriptc.300G>A p.Ala100= synonymous_variant 2/5 ENST00000379044.5 NP_620689.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARXENST00000379044.5 linkuse as main transcriptc.300G>A p.Ala100= synonymous_variant 2/51 NM_139058.3 ENSP00000368332 P1

Frequencies

GnomAD3 genomes
AF:
0.0000367
AC:
4
AN:
109067
Hom.:
0
Cov.:
23
AF XY:
0.0000611
AC XY:
2
AN XY:
32745
show subpopulations
Gnomad AFR
AF:
0.0000655
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000733
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000487
AC:
38
AN:
779905
Hom.:
0
Cov.:
32
AF XY:
0.0000681
AC XY:
16
AN XY:
234939
show subpopulations
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:
0.00246
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000148
Gnomad4 OTH exome
AF:
0.0000995
GnomAD4 genome
AF:
0.0000367
AC:
4
AN:
109067
Hom.:
0
Cov.:
23
AF XY:
0.0000611
AC XY:
2
AN XY:
32745
show subpopulations
Gnomad4 AFR
AF:
0.0000655
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000733
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
1
Bravo
AF:
0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 14, 2015- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 30, 2020- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 18, 2014- -
Intellectual disability, X-linked, with or without seizures, arx-related;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 09, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
CADD
Benign
5.6
DANN
Benign
0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797045294; hg19: chrX-25031812; API