X-77508138-G-A

Variant names:

• chrX-77508138-G-A
• rs3027524
• NM_000489.6:c.*213C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000489.6(ATRX):​c.*213C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 421,363 control chromosomes in the GnomAD database, including 12 homozygotes. There are 262 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., 173 hem., cov: 22)
  • Exomes 𝑓: 0.00097 (3 hom. 89 hem.)
• Consequence: ATRX NM_000489.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.15
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-77508138-G-A is Benign according to our data. Variant chrX-77508138-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1199087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00634 (693/109357) while in subpopulation AFR AF = 0.0217 (653/30116). AF 95% confidence interval is 0.0203. There are 9 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.*213C>T		3_prime_UTR	Exon 35 of 35	NP_000480.3
	ATRX	NM_138270.5		c.*213C>T		3_prime_UTR	Exon 34 of 34	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.*213C>T		3_prime_UTR	Exon 35 of 35	ENSP00000362441.4	P46100-1
	ATRX	ENST00000395603.7	TSL:1	c.*213C>T		3_prime_UTR	Exon 34 of 34	ENSP00000378967.3	P46100-4
	ATRX	ENST00000480283.5	TSL:1	n.*7320C>T		non_coding_transcript_exon	Exon 36 of 36	ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 689 AN: 109311 Hom.: 9 Cov.: 22

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00215

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000798

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00543

GnomAD4 exome AF: 0.000968 AC: 302 AN: 312006 Hom.: 3 Cov.: 4 AF XY: 0.000907 AC XY: 89 AN XY: 98106

African (AFR) AF: 0.0224 AC: 212 AN: 9447

American (AMR) AF: 0.00168 AC: 21 AN: 12488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9510

East Asian (EAS) AF: 0.000181 AC: 4 AN: 22091

South Asian (SAS) AF: 0.0000873 AC: 2 AN: 22920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20174

Middle Eastern (MID) AF: 0.00152 AC: 2 AN: 1316

European-Non Finnish (NFE) AF: 0.000138 AC: 27 AN: 195319

Other (OTH) AF: 0.00181 AC: 34 AN: 18741

GnomAD4 genome AF: 0.00634 AC: 693 AN: 109357 Hom.: 9 Cov.: 22 AF XY: 0.00545 AC XY: 173 AN XY: 31719

African (AFR) AF: 0.0217 AC: 653 AN: 30116

American (AMR) AF: 0.00215 AC: 22 AN: 10225

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2620

East Asian (EAS) AF: 0.00 AC: 0 AN: 3489

South Asian (SAS) AF: 0.000801 AC: 2 AN: 2497

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5497

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

European-Non Finnish (NFE) AF: 0.000152 AC: 8 AN: 52521

Other (OTH) AF: 0.00536 AC: 8 AN: 1492

Alfa AF: 0.000502 Hom.: 1

Bravo AF: 0.00708

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs3027524; hg19: chrX-76763616;