rs797044563

Variant names:

• chrX-77683154-C-A
• rs797044563
• NM_000489.6:c.2102G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-77683154-C-A
• chrX-77683154-C-G
• chrX-77683154-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000489.6(ATRX):​c.2102G>T​(p.Arg701Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. R701H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 4 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-77683154-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191250.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34885022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.2102G>T	p.Arg701Leu	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.2102G>T	p.Arg701Leu	missense_variant	Exon 9 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000548 AC: 1 AN: 182477 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	.;.;T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.73	D
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D;D;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.041	D;D;T;.
Polyphen		1.0	D;.;.;.
Vest4		0.33
MutPred		0.18		Gain of ubiquitination at K700 (P = 0.0311);.;.;.;
MVP		0.86
MPC		0.058
ClinPred		0.78	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.25
Mutation Taster		=91/9	polymorphism

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: rs797044563; hg19: chrX-76938646; COSMIC: COSV64871348;