X-77620396-C-G

Variant names:

• chrX-77620396-C-G
• rs141240580
• NM_000489.6:c.5271G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000489.6(ATRX):​c.5271G>C​(p.Glu1757Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1757E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATRX NM_000489.6 missense, splice_region
• Scores: Splicing: ADA: 0.0001215
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.793
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), 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: Likely_pathogenic. The variant received 9 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, 4 uncertain in NM_000489.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant X-77620396-C-G is Pathogenic according to our data. Variant chrX-77620396-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520958.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000489.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	NM_000489.6	MANE Select	c.5271G>C	p.Glu1757Asp	missense splice_region	Exon 20 of 35	NP_000480.3
	ATRX	NM_138270.5		c.5157G>C	p.Glu1719Asp	missense splice_region	Exon 19 of 34	NP_612114.2	P46100-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	ENST00000373344.11	TSL:1 MANE Select	c.5271G>C	p.Glu1757Asp	missense splice_region	Exon 20 of 35	ENSP00000362441.4	P46100-1
	ATRX	ENST00000395603.7	TSL:1	c.5157G>C	p.Glu1719Asp	missense splice_region	Exon 19 of 34	ENSP00000378967.3	P46100-4
	ATRX	ENST00000480283.5	TSL:1	n.*4899G>C		splice_region non_coding_transcript_exon	Exon 21 of 36	ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Alpha thalassemia-X-linked intellectual disability syndrome (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.57	T
PhyloP100		0.79
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.79
Sift	Benign	0.037	D
Sift4G	Pathogenic	0.0	D
Vest4		0.75
MutPred		0.90		Gain of relative solvent accessibility (P = 0.2363)
MVP		0.95
MPC		2.5
ClinPred		0.99	D
GERP RS		0.66
gMVP		0.98
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.18
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: rs141240580; hg19: chrX-76875864;