X-77599584-AAAACAAACAAAC-AAAACAAACAAACAAAC

Variant names:

• chrX-77599584-A-AAAAC
• rs782072699
• NM_000489.6:c.5787-8_5787-5dupGTTT

Variant summary

Our verdict is Benign. The variant received -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
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), 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 -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 Benign/Likely_benign. ClinVar VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 34 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	NM_000489.6	MANE Select	c.5787-8_5787-5dupGTTT		splice_region intron	N/A	NP_000480.3
	ATRX	NM_138270.5		c.5673-8_5673-5dupGTTT		splice_region intron	N/A	NP_612114.2	P46100-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	ENST00000373344.11	TSL:1 MANE Select	c.5787-5_5787-4insGTTT		splice_region intron	N/A	ENSP00000362441.4	P46100-1
	ATRX	ENST00000395603.7	TSL:1	c.5673-5_5673-4insGTTT		splice_region intron	N/A	ENSP00000378967.3	P46100-4
	ATRX	ENST00000480283.5	TSL:1	n.*5415-5_*5415-4insGTTT		splice_region intron	N/A	ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes AF: 0.0000363 AC: 4 AN: 110128 Hom.: 0 Cov.: 22

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

GnomAD2 exomes AF: 0.000104 AC: 19 AN: 182545 AF XY: 0.000148

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 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

African (AFR) AF: 0.000152 AC: 4 AN: 26344

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30174

South Asian (SAS) AF: 0.000666 AC: 36 AN: 54091

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000321 AC: 27 AN: 841070

Other (OTH) AF: 0.0000869 AC: 4 AN: 46051

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

African (AFR) AF: 0.0000330 AC: 1 AN: 30274

American (AMR) AF: 0.00 AC: 0 AN: 10171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3526

South Asian (SAS) AF: 0.00 AC: 0 AN: 2578

European-Finnish (FIN) AF: 0.000173 AC: 1 AN: 5764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52830

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alpha thalassemia-X-linked intellectual disability syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs782072699; hg19: chrX-76855053; COSMIC: COSV64877565; COSMIC: COSV64877565;