rs782553856

Variant names:

• chrX-77698596-A-G
• rs782553856
• ENST00000623321.3:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-77698596-A-G
• chrX-77698596-A-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PVS1_Supporting BP6_Moderate

The ENST00000623321.3(ATRX):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,093,154 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 0 hem.)
• Consequence: ATRX ENST00000623321.3 start_lost
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.07
• 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: 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.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 2 codons. Genomic position: 77698594. Lost 0.003 part of the original CDS.
• BP6: Variant X-77698596-A-G is Benign according to our data. Variant chrX-77698596-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1596846.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.167T>C	p.Met56Thr	missense_variant	Exon 3 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.167T>C	p.Met56Thr	missense_variant	Exon 3 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182739 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 9 AN: 1093154 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 359160

African (AFR) AF: 0.00 AC: 0 AN: 26308

American (AMR) AF: 0.00 AC: 0 AN: 35119

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19310

East Asian (EAS) AF: 0.00 AC: 0 AN: 30093

South Asian (SAS) AF: 0.00 AC: 0 AN: 53951

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4095

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 837883

Other (OTH) AF: 0.00 AC: 0 AN: 45909

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	.;.;T;T;.;T;.
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.82	T;.;T;T;D;D;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.071	T
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.27	N;N;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.18	T;T;.;.;.;.;.
Sift4G	Benign	0.53	T;T;T;.;D;D;.
Polyphen		0.26	B;.;.;.;.;.;.
Vest4		0.39
MutPred		0.14		Gain of phosphorylation at M56 (P = 0.0186);Gain of phosphorylation at M56 (P = 0.0186);Gain of phosphorylation at M56 (P = 0.0186);Gain of phosphorylation at M56 (P = 0.0186);.;.;.;
MVP		0.90
MPC		1.3
ClinPred		0.19	T
GERP RS		3.5
PromoterAI		0.029	Neutral
gMVP		0.059
Mutation Taster		=83/17	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: rs782553856; hg19: chrX-76954084;