X-77508138-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.*213C>T		3_prime_UTR_variant	35/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.*213C>T		3_prime_UTR_variant	35/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 689 AN: 109311 Hom.: 9 Cov.: 22 AF XY: 0.00540 AC XY: 171 AN XY: 31663

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

Gnomad4 AFR exome AF: 0.0224

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000181

Gnomad4 SAS exome AF: 0.0000873

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00181

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

Gnomad4 AFR AF: 0.0217

Gnomad4 AMR AF: 0.00215

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000801

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000152

Gnomad4 OTH AF: 0.00536

Alfa AF: 0.000502 Hom.: 1

Bravo AF: 0.00708

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	15
Dann	Benign	0.84

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: rs3027524; hg19: chrX-76763616;