Genetic Variant NM_139058.3:c.-83C>A (chrX-25015820-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_139058.3(ARX):c.-83C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 986,350 control chromosomes in the GnomAD database, including 9 homozygotes. There are 682 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 43 hem., cov: 24)

Exomes 𝑓: 0.0025 ( 9 hom. 639 hem. )

Consequence

ARX
NM_139058.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.874

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]

ARX links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant X-25015820-G-T is Benign according to our data. Variant chrX-25015820-G-T is described in ClinVar as [Benign]. Clinvar id is 446864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00163 (184/112801) while in subpopulation NFE AF= 0.0019 (101/53280). AF 95% confidence interval is 0.0016. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 43 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.-83C>A		5_prime_UTR_variant	Exon 1 of 5	ENST00000379044.5	NP_620689.1	Q96QS3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARX	ENST00000379044.5 link	c.-83C>A	5_prime_UTR_variant	Exon 1 of 5	1	NM_139058.3	ENSP00000368332.4	Q96QS3
ARX	ENST00000636609.1 link	n.36-175C>A	intron_variant	Intron 1 of 1	5
ARX	ENST00000637394.1 link	n.68-175C>A	intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

185

AN:

112747

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

34891

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000835

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00221

Gnomad FIN

AF:

0.000160

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00132

GnomAD4 exome

AF:

0.00246

AC:

2147

AN:

873549

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

639

AN XY:

231891

show subpopulations

Gnomad4 AFR exome

AF:

0.000327

Gnomad4 AMR exome

AF:

0.000576

Gnomad4 ASJ exome

AF:

0.0206

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00354

Gnomad4 FIN exome

AF:

0.000319

Gnomad4 NFE exome

AF:

0.00222

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.00163

AC:

184

AN:

112801

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

34955

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000834

Gnomad4 ASJ

AF:

0.0208

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00185

Gnomad4 FIN

AF:

0.000160

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.000920

Hom.:

Bravo

AF:

0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 24, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.88

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over