rs587780288

chrX-77652318-CTCT-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000489.6(ATRX):c.4350_4352del(p.Glu1464del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,204,640 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1450E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000032 (0 hom. 12 hem.)
• Consequence: ATRX NM_000489.6 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.50

Genes affected

ATRX (HGNC:886): (ATRX chromatin remodeler) The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis. Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as alpha-thalassemia (ATRX) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-77652318-CTCT-C is Benign according to our data. Variant chrX-77652318-CTCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128497.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000032 (35/1094344) while in subpopulation SAS AF= 0.00024 (13/54105). AF 95% confidence interval is 0.000142. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.4350_4352del	p.Glu1464del	inframe_deletion	15/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.4350_4352del	p.Glu1464del	inframe_deletion	15/35	1	NM_000489.6	P3
ATRX	ENST00000395603.7	c.4236_4238del	p.Glu1426del	inframe_deletion	14/34	1		A2
ATRX	ENST00000480283.5	c.*3978_*3980del		3_prime_UTR_variant, NMD_transcript_variant	16/36	1
ATRX	ENST00000623242.3			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000272 AC: 3 AN: 110296 Hom.: 0 Cov.: 21 AF XY: 0.0000307 AC XY: 1 AN XY: 32560

Gnomad AFR AF: 0.0000660

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000553 AC: 10 AN: 180879 Hom.: 0 AF XY: 0.0000452 AC XY: 3 AN XY: 66305

Gnomad AFR exome AF: 0.0000769

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000320 AC: 35 AN: 1094344 Hom.: 0 AF XY: 0.0000333 AC XY: 12 AN XY: 360612

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000272 AC: 3 AN: 110296 Hom.: 0 Cov.: 21 AF XY: 0.0000307 AC XY: 1 AN XY: 32560

Gnomad4 AFR AF: 0.0000660

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000383

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 13, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2014	- -

Alpha thalassemia-X-linked intellectual disability syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587780288; hg19: chrX-76907808;