X-77682471-C-G

Variant names:

• chrX-77682471-C-G
• rs3088074
• NM_000489.6:c.2785G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000489.6(ATRX):​c.2785G>C​(p.Glu929Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 110,313 control chromosomes in the GnomAD database, including 12,893 homozygotes. There are 16,657 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E929D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.52 (12893 hom., 16657 hem., cov: 22)
  • Exomes 𝑓: 0.67 (169861 hom. 241450 hem.)
  • Failed GnomAD Quality Control
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.280
• Publications: 65 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006577015).
• BP6: Variant X-77682471-C-G is Benign according to our data. Variant chrX-77682471-C-G is described in ClinVar as Benign. ClinVar VariationId is 237852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.2785G>C	p.Glu929Gln	missense_variant	Exon 9 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.2785G>C	p.Glu929Gln	missense_variant	Exon 9 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes AF: 0.516 AC: 56915 AN: 110260 Hom.: 12906 Cov.: 22

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.552

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.669 AC: 734383 AN: 1097922 Hom.: 169861 Cov.: 51 AF XY: 0.665 AC XY: 241450 AN XY: 363332

African (AFR) AF: 0.118 AC: 3122 AN: 26388

American (AMR) AF: 0.736 AC: 25886 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 13492 AN: 19381

East Asian (EAS) AF: 0.511 AC: 15437 AN: 30198

South Asian (SAS) AF: 0.496 AC: 26863 AN: 54134

European-Finnish (FIN) AF: 0.683 AC: 27634 AN: 40486

Middle Eastern (MID) AF: 0.562 AC: 2324 AN: 4137

European-Non Finnish (NFE) AF: 0.701 AC: 590075 AN: 841919

Other (OTH) AF: 0.641 AC: 29550 AN: 46084

GnomAD4 genome AF: 0.516 AC: 56903 AN: 110313 Hom.: 12893 Cov.: 22 AF XY: 0.511 AC XY: 16657 AN XY: 32619

African (AFR) AF: 0.132 AC: 4029 AN: 30590

American (AMR) AF: 0.628 AC: 6483 AN: 10329

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 1857 AN: 2611

East Asian (EAS) AF: 0.528 AC: 1823 AN: 3453

South Asian (SAS) AF: 0.504 AC: 1309 AN: 2598

European-Finnish (FIN) AF: 0.681 AC: 3893 AN: 5718

Middle Eastern (MID) AF: 0.523 AC: 112 AN: 214

European-Non Finnish (NFE) AF: 0.685 AC: 36078 AN: 52640

Other (OTH) AF: 0.551 AC: 819 AN: 1487

Alfa AF: 0.660 Hom.: 25457

Bravo AF: 0.504

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.93
CADD	Benign	17
DEOGEN2	Benign	0.021	.;.;T;T
LIST_S2	Benign	0.70	T;.;T;T
MetaRNN	Benign	0.0066	T;T;T;T
PhyloP100		0.28
Sift4G	Benign	0.18	T;T;D;.
Vest4		0.10
PromoterAI		-0.0064	Neutral
gMVP		0.12

Splicing

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

Other links and lift over

dbSNP: rs3088074; hg19: chrX-76937963;