X-77654205-C-T

Variant names:

• chrX-77654205-C-T
• rs111833322
• NM_000489.6:c.4215-5G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000489.6(ATRX):​c.4215-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,185,355 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 53 hem.)
• Consequence: ATRX NM_000489.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001036
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.06
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant X-77654205-C-T is Benign according to our data. Variant chrX-77654205-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 533635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000179 (20/111602) while in subpopulation AMR AF = 0.000856 (9/10519). AF 95% confidence interval is 0.000445. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.4215-5G>A		splice_region_variant, intron_variant	Intron 13 of 34	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.4215-5G>A		splice_region_variant, intron_variant	Intron 13 of 34	1	NM_000489.6	ENSP00000362441.4
ATRX	ENST00000395603.7	c.4101-5G>A		splice_region_variant, intron_variant	Intron 12 of 33	1		ENSP00000378967.3
ATRX	ENST00000624166.3	c.4011-5G>A		splice_region_variant, intron_variant	Intron 13 of 13	1		ENSP00000485103.1
ATRX	ENST00000480283.5	n.*3843-5G>A		splice_region_variant, intron_variant	Intron 14 of 35	1		ENSP00000480196.1

Frequencies

GnomAD3 genomes AF: 0.000170 AC: 19 AN: 111550 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000857

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: 0.0000755

Gnomad OTH AF: 0.000667

GnomAD2 exomes AF: 0.000143 AC: 26 AN: 181292 AF XY: 0.000181

Gnomad AFR exome AF: 0.000306

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000157 AC: 169 AN: 1073753 Hom.: 0 Cov.: 26 AF XY: 0.000155 AC XY: 53 AN XY: 341085

African (AFR) AF: 0.000693 AC: 18 AN: 25968

American (AMR) AF: 0.000370 AC: 13 AN: 35118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19168

East Asian (EAS) AF: 0.00 AC: 0 AN: 29988

South Asian (SAS) AF: 0.0000748 AC: 4 AN: 53490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.000146 AC: 120 AN: 821146

Other (OTH) AF: 0.000309 AC: 14 AN: 45296

GnomAD4 genome AF: 0.000179 AC: 20 AN: 111602 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 33940

African (AFR) AF: 0.000195 AC: 6 AN: 30807

American (AMR) AF: 0.000856 AC: 9 AN: 10519

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00 AC: 0 AN: 2724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000755 AC: 4 AN: 52949

Other (OTH) AF: 0.000658 AC: 1 AN: 1520

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.000366

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Aug 18, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.0
DANN	Benign	0.87
PhyloP100		1.1
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.048
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: rs111833322; hg19: chrX-76909695;