X-77599584-AAAACAAAC-AAAACAAACAAAC

Position:

• chrX-77599584-AAAACAAAC-AAAACAAACAAAC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000489.6(ATRX):​c.5787-8_5787-5dupGTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,207,113 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000067 (0 hom. 34 hem.)
• Consequence: ATRX NM_000489.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.25

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 -16 ACMG points.

• BP6: Variant X-77599584-A-AAAAC is Benign according to our data. Variant chrX-77599584-A-AAAAC is described in ClinVar as [Likely_benign]. Clinvar id is 707287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000675 (74/1096943) while in subpopulation SAS AF= 0.000666 (36/54091). AF 95% confidence interval is 0.000493. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6	c.5787-8_5787-5dupGTTT		splice_region_variant, intron_variant		ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.5787-8_5787-5dupGTTT		splice_region_variant, intron_variant		1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes AF: 0.0000363 AC: 4 AN: 110128 Hom.: 0 Cov.: 22 AF XY: 0.0000618 AC XY: 2 AN XY: 32376

Gnomad AFR AF: 0.0000331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 19 AN: 182545 Hom.: 0 AF XY: 0.000148 AC XY: 10 AN XY: 67413

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.000788

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000675 AC: 74 AN: 1096943 Hom.: 0 Cov.: 31 AF XY: 0.0000938 AC XY: 34 AN XY: 362457

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000666

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.0000321

Gnomad4 OTH exome AF: 0.0000869

GnomAD4 genome AF: 0.0000363 AC: 4 AN: 110170 Hom.: 0 Cov.: 22 AF XY: 0.0000617 AC XY: 2 AN XY: 32428

Gnomad4 AFR AF: 0.0000330

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000284

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000173

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs782072699; hg19: chrX-76855053;