X-77599826-GA-GAA

Variant names:

• chrX-77599826-G-GA
• rs781820607
• NM_000489.6:c.5698-7dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000489.6(ATRX):​c.5698-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 1,126,320 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00092 (0 hom. 7 hem.)
• Consequence: ATRX NM_000489.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.358
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-77599826-G-GA is Benign according to our data. Variant chrX-77599826-G-GA is described in ClinVar as Benign. ClinVar VariationId is 533633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

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.5698-7dupT		splice_region intron	N/A	NP_000480.3
	ATRX	NM_138270.5		c.5584-7dupT		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_5698-6insT		splice_region intron	N/A	ENSP00000362441.4
	ATRX	ENST00000395603.7	TSL:1	c.5584-7_5584-6insT		splice_region intron	N/A	ENSP00000378967.3
	ATRX	ENST00000480283.5	TSL:1	n.*5326-7_*5326-6insT		splice_region intron	N/A	ENSP00000480196.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 19 AN: 107633 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000100

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: 0.0000966

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000142 AC: 22 AN: 154675 AF XY: 0.0000385

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.000131

Gnomad ASJ exome AF: 0.000308

Gnomad EAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000925 AC: 942 AN: 1018637 Hom.: 0 Cov.: 26 AF XY: 0.0000228 AC XY: 7 AN XY: 307107

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

African (AFR) AF: 0.00107 AC: 26 AN: 24327

American (AMR) AF: 0.000152 AC: 5 AN: 32922

Ashkenazi Jewish (ASJ) AF: 0.000384 AC: 7 AN: 18243

East Asian (EAS) AF: 0.000279 AC: 8 AN: 28702

South Asian (SAS) AF: 0.000362 AC: 18 AN: 49663

European-Finnish (FIN) AF: 0.000127 AC: 5 AN: 39393

Middle Eastern (MID) AF: 0.000265 AC: 1 AN: 3770

European-Non Finnish (NFE) AF: 0.00108 AC: 844 AN: 778500

Other (OTH) AF: 0.000649 AC: 28 AN: 43117

⚠️ 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 AF: 0.000176 AC: 19 AN: 107683 Hom.: 0 Cov.: 22 AF XY: 0.000161 AC XY: 5 AN XY: 31009

African (AFR) AF: 0.000437 AC: 13 AN: 29732

American (AMR) AF: 0.0000999 AC: 1 AN: 10012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2597

East Asian (EAS) AF: 0.00 AC: 0 AN: 3452

South Asian (SAS) AF: 0.00 AC: 0 AN: 2526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 205

European-Non Finnish (NFE) AF: 0.0000966 AC: 5 AN: 51749

Other (OTH) AF: 0.00 AC: 0 AN: 1471

Alfa AF: 0.00722 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
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: rs781820607; hg19: chrX-76855295;