X-77656597-C-T

Variant names:

• chrX-77656597-C-T
• rs147331649
• NM_000489.6:c.4177G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000489.6(ATRX):​c.4177G>A​(p.Val1393Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,206,743 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. V1393L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 0 hem.)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2719603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.4177G>A	p.Val1393Ile	missense_variant	Exon 13 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.4177G>A	p.Val1393Ile	missense_variant	Exon 13 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111760 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1094983 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361265

African (AFR) AF: 0.00 AC: 0 AN: 26354

American (AMR) AF: 0.00 AC: 0 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30077

South Asian (SAS) AF: 0.00 AC: 0 AN: 53337

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3889

European-Non Finnish (NFE) AF: 0.00000714 AC: 6 AN: 840497

Other (OTH) AF: 0.00 AC: 0 AN: 45939

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111760 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33950

African (AFR) AF: 0.00 AC: 0 AN: 30788

American (AMR) AF: 0.00 AC: 0 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2719

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5973

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53146

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.020	.;.;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	0.58	D
PhyloP100		2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.37	N;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.30	T;T;T
Vest4		0.12
MVP		0.87
MPC		1.1
ClinPred		0.57	D
GERP RS		5.2
gMVP		0.065
Mutation Taster		=86/14	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: rs147331649; hg19: chrX-76912087;