NM_000489.6:c.2513A>G

Variant names:

• chrX-77682743-T-C
• rs587778085
• NM_000489.6:c.2513A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000489.6(ATRX):​c.2513A>G​(p.Lys838Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 111,282 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: -0.0400
• Publications: 2 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15050173).
• BP6: Variant X-77682743-T-C is Benign according to our data. Variant chrX-77682743-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133648.

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.2513A>G	p.Lys838Arg	missense	Exon 9 of 35	NP_000480.3
	ATRX	NM_138270.5		c.2399A>G	p.Lys800Arg	missense	Exon 8 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.2513A>G	p.Lys838Arg	missense	Exon 9 of 35	ENSP00000362441.4	P46100-1
	ATRX	ENST00000395603.7	TSL:1	c.2399A>G	p.Lys800Arg	missense	Exon 8 of 34	ENSP00000378967.3	P46100-4
	ATRX	ENST00000624166.3	TSL:1	c.2309A>G	p.Lys770Arg	missense	Exon 9 of 14	ENSP00000485103.1	A0A096LNL9

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111282 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111282 Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1 AN XY: 33504

African (AFR) AF: 0.0000326 AC: 1 AN: 30638

American (AMR) AF: 0.00 AC: 0 AN: 10452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52953

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.00 Hom.: 0

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 provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.5
DANN	Benign	0.73
DEOGEN2	Benign	0.017	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.51	T
PhyloP100		-0.040
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.10
MutPred		0.14		Loss of methylation at K838 (P = 0.048)
MVP		0.74
MPC		0.022
ClinPred		0.064	T
GERP RS		1.2
gMVP		0.13
Mutation Taster		=88/12	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: rs587778085; hg19: chrX-76938235;