X-77599826-GA-GAA

Position:

• chrX-77599826-GA-GAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000489.6(ATRX):​c.5698-7_5698-6insT variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.358

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 -10 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 id is 533633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000176 (19/107683) while in subpopulation AFR AF= 0.000437 (13/29732). AF 95% confidence interval is 0.000259. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.5698-7_5698-6insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.5698-7_5698-6insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000489.6	P3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 19 AN: 107633 Hom.: 0 Cov.: 22 AF XY: 0.000162 AC XY: 5 AN XY: 30949

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

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

Gnomad4 AFR exome AF: 0.00107

Gnomad4 AMR exome AF: 0.000152

Gnomad4 ASJ exome AF: 0.000384

Gnomad4 EAS exome AF: 0.000279

Gnomad4 SAS exome AF: 0.000362

Gnomad4 FIN exome AF: 0.000127

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.000649

GnomAD4 genome AF: 0.000176 AC: 19 AN: 107683 Hom.: 0 Cov.: 22 AF XY: 0.000161 AC XY: 5 AN XY: 31009

Gnomad4 AFR AF: 0.000437

Gnomad4 AMR AF: 0.0000999

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000966

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

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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: rs781820607; hg19: chrX-76855295;