X-77599826-GA-GAAA

Variant names:

• chrX-77599826-G-GAA
• rs781820607
• NM_000489.6:c.5698-8_5698-7dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000489.6(ATRX):​c.5698-8_5698-7dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000968 in 1,032,550 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.7e-7 (0 hom. 0 hem.)
• Consequence: ATRX NM_000489.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.358
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000489.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	NM_000489.6	MANE Select	c.5698-8_5698-7dupTT		splice_region intron	N/A	NP_000480.3
	ATRX	NM_138270.5		c.5584-8_5584-7dupTT		splice_region intron	N/A	NP_612114.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	ENST00000373344.11	TSL:1 MANE Select	c.5698-7_5698-6insTT		splice_region intron	N/A	ENSP00000362441.4
	ATRX	ENST00000395603.7	TSL:1	c.5584-7_5584-6insTT		splice_region intron	N/A	ENSP00000378967.3
	ATRX	ENST00000480283.5	TSL:1	n.*5326-7_*5326-6insTT		splice_region intron	N/A	ENSP00000480196.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.68e-7 AC: 1 AN: 1032550 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 314758

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24669

American (AMR) AF: 0.00 AC: 0 AN: 33285

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18493

East Asian (EAS) AF: 0.00 AC: 0 AN: 29125

South Asian (SAS) AF: 0.00 AC: 0 AN: 50620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3815

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 789101

Other (OTH) AF: 0.00 AC: 0 AN: 43680

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

Splicing

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

Other links and lift over

dbSNP: rs781820607; hg19: chrX-76855295;