rs782274478

Variant names:

• chrX-77522351-T-A
• rs782274478
• NM_000489.6:c.6887A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-77522351-T-A
• chrX-77522351-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000489.6(ATRX):​c.6887A>T​(p.Asn2296Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,916 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2296S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.6887A>T	p.Asn2296Ile	missense_variant	Exon 32 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.6887A>T	p.Asn2296Ile	missense_variant	Exon 32 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096916 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362570

African (AFR) AF: 0.00 AC: 0 AN: 26368

American (AMR) AF: 0.00 AC: 0 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841033

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.0	.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.0	.;.
PhyloP100		1.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.53
ClinPred		0.82	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.72
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782274478; hg19: chrX-76777829;