X-77681615-T-C

Variant names:

• chrX-77681615-T-C
• rs144527582
• NM_000489.6:c.3641A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000489.6(ATRX):​c.3641A>G​(p.Asn1214Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000664 in 1,204,998 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1214I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.35
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24608102).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	NM_000489.6	MANE Select	c.3641A>G	p.Asn1214Ser	missense	Exon 9 of 35	NP_000480.3
	ATRX	NM_138270.5		c.3527A>G	p.Asn1176Ser	missense	Exon 8 of 34	NP_612114.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	ENST00000373344.11	TSL:1 MANE Select	c.3641A>G	p.Asn1214Ser	missense	Exon 9 of 35	ENSP00000362441.4
	ATRX	ENST00000395603.7	TSL:1	c.3527A>G	p.Asn1176Ser	missense	Exon 8 of 34	ENSP00000378967.3
	ATRX	ENST00000624166.3	TSL:1	c.3437A>G	p.Asn1146Ser	missense	Exon 9 of 14	ENSP00000485103.1

Frequencies

GnomAD3 genomes AF: 0.0000359 AC: 4 AN: 111461 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000130

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 AF: 0.00000366 AC: 4 AN: 1093537 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 1 AN XY: 359659

African (AFR) AF: 0.00 AC: 0 AN: 26142

American (AMR) AF: 0.0000290 AC: 1 AN: 34504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19193

East Asian (EAS) AF: 0.00 AC: 0 AN: 30127

South Asian (SAS) AF: 0.00 AC: 0 AN: 52756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840393

Other (OTH) AF: 0.0000436 AC: 2 AN: 45906

GnomAD4 genome AF: 0.0000359 AC: 4 AN: 111461 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33681

African (AFR) AF: 0.000130 AC: 4 AN: 30738

American (AMR) AF: 0.00 AC: 0 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2647

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52930

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Alpha thalassemia-X-linked intellectual disability syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.041	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.31	D
PhyloP100		4.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.49	T
Polyphen		0.55	P
Vest4		0.15
MutPred		0.24		Gain of phosphorylation at N1214 (P = 0.0021)
MVP		0.82
MPC		0.028
ClinPred		0.47	T
GERP RS		5.7
gMVP		0.076
Mutation Taster		=93/7	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: rs144527582; hg19: chrX-76937107;