rs1309299805

Variant names:

• chrX-77593681-T-C
• rs1309299805
• NM_000489.6:c.6110+15A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000489.6(ATRX):​c.6110+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,192,738 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 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 0.000045 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000056 (0 hom. 24 hem.)
• Consequence: ATRX NM_000489.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.693
• Publications: 0 publications found

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]

ATRX Gene-Disease associations (from GenCC):

• alpha thalassemia-X-linked intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• ATR-X-related syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability-hypotonic facies syndrome, X-linked, 1

  Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-77593681-T-C is Benign according to our data. Variant chrX-77593681-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445732.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.6110+15A>G		intron_variant	Intron 26 of 34	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.6110+15A>G		intron_variant	Intron 26 of 34	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111862 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000552 AC: 1 AN: 181307 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000555 AC: 60 AN: 1080876 Hom.: 0 Cov.: 27 AF XY: 0.0000688 AC XY: 24 AN XY: 348926

African (AFR) AF: 0.00 AC: 0 AN: 26027

American (AMR) AF: 0.00 AC: 0 AN: 35094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19245

East Asian (EAS) AF: 0.00 AC: 0 AN: 30079

South Asian (SAS) AF: 0.0000563 AC: 3 AN: 53323

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40453

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.0000665 AC: 55 AN: 827063

Other (OTH) AF: 0.0000440 AC: 2 AN: 45503

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111862 Hom.: 0 Cov.: 22 AF XY: 0.0000881 AC XY: 3 AN XY: 34038

African (AFR) AF: 0.0000325 AC: 1 AN: 30757

American (AMR) AF: 0.00 AC: 0 AN: 10515

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3600

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53201

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.000145 Hom.: 2

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jun 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alpha thalassemia-X-linked intellectual disability syndrome Benign:1

Sep 21, 2024

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
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.8
DANN	Benign	0.84
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1309299805; hg19: chrX-76849151;