rs25641

Variant names:

• chrX-77635955-A-G
• rs25641
• NM_000489.6:c.4659T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-77635955-A-G
• chrX-77635955-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000489.6(ATRX):​c.4659T>C​(p.His1553His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,206,214 control chromosomes in the GnomAD database, including 810 homozygotes. There are 3,410 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (395 hom., 1649 hem., cov: 23)
  • Exomes 𝑓: 0.0060 (415 hom. 1761 hem.)
• Consequence: ATRX NM_000489.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.65
• Publications: 4 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-77635955-A-G is Benign according to our data. Variant chrX-77635955-A-G is described in ClinVar as Benign. ClinVar VariationId is 93140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

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.4659T>C	p.His1553His	synonymous	Exon 16 of 35	NP_000480.3
	ATRX	NM_138270.5		c.4545T>C	p.His1515His	synonymous	Exon 15 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.4659T>C	p.His1553His	synonymous	Exon 16 of 35	ENSP00000362441.4	P46100-1
	ATRX	ENST00000395603.7	TSL:1	c.4545T>C	p.His1515His	synonymous	Exon 15 of 34	ENSP00000378967.3	P46100-4
	ATRX	ENST00000480283.5	TSL:1	n.*4287T>C		non_coding_transcript_exon	Exon 17 of 36	ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 6053 AN: 112054 Hom.: 394 Cov.: 23

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0170

Gnomad NFE AF: 0.000526

Gnomad OTH AF: 0.0414

GnomAD2 exomes AF: 0.0157 AC: 2820 AN: 179749 AF XY: 0.00998

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.00725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.00764

GnomAD4 exome AF: 0.00603 AC: 6600 AN: 1094109 Hom.: 415 Cov.: 29 AF XY: 0.00489 AC XY: 1761 AN XY: 359963

African (AFR) AF: 0.202 AC: 5304 AN: 26300

American (AMR) AF: 0.00900 AC: 316 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19303

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.000502 AC: 27 AN: 53818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40472

Middle Eastern (MID) AF: 0.0101 AC: 38 AN: 3754

European-Non Finnish (NFE) AF: 0.000282 AC: 237 AN: 839255

Other (OTH) AF: 0.0148 AC: 678 AN: 45918

GnomAD4 genome AF: 0.0541 AC: 6061 AN: 112105 Hom.: 395 Cov.: 23 AF XY: 0.0481 AC XY: 1649 AN XY: 34285

African (AFR) AF: 0.187 AC: 5735 AN: 30699

American (AMR) AF: 0.0216 AC: 230 AN: 10647

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3591

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6113

Middle Eastern (MID) AF: 0.0186 AC: 4 AN: 215

European-Non Finnish (NFE) AF: 0.000526 AC: 28 AN: 53250

Other (OTH) AF: 0.0409 AC: 63 AN: 1539

Alfa AF: 0.0467 Hom.: 231

Bravo AF: 0.0637

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Alpha thalassemia-X-linked intellectual disability syndrome (2)
-	-	2	not provided (2)
-	-	1	Acquired hemoglobin H disease;C1845055:Alpha thalassemia-X-linked intellectual disability syndrome;C4759781:Intellectual disability-hypotonic facies syndrome, X-linked, 1 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.1
DANN	Benign	0.48
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs25641; hg19: chrX-76891446; COSMIC: COSV64873454;