rs122445111

Variant names:

• chrX-77684942-C-T
• rs122445111
• NM_000489.6:c.659G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000489.6(ATRX):​c.659G>A​(p.Cys220Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C220R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.54
• Publications: 7 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000489.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-77684942-C-T is Pathogenic according to our data. Variant chrX-77684942-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.659G>A	p.Cys220Tyr	missense_variant	Exon 8 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.659G>A	p.Cys220Tyr	missense_variant	Exon 8 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jun 06, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Aug 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATRX c.659G>A (p.Cys220Tyr) results in a non-conservative amino acid change located in the ADD domain (IPR025766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183067 control chromosomes (gnomAD). c.659G>A has been reported in the literature co-segregating with disease in a family with multiple individuals affected with ATR-X Syndrome (Stevenson_2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Intellectual disability-hypotonic facies syndrome, X-linked Pathogenic:1

Oct 23, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;.;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.5
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.8	D;D;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.93
MutPred		0.94		Gain of loop (P = 0.0851);.;.;Gain of loop (P = 0.0851);.;
MVP		1.0
MPC		3.0
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs122445111; hg19: chrX-76940434;