rs199929884

Variant names:

• chrX-77683789-G-A
• rs199929884
• NM_000489.6:c.1467C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-77683789-G-A
• chrX-77683789-G-C
• chrX-77683789-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000489.6(ATRX):​c.1467C>T​(p.Thr489Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,207,535 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 108 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.00028 (0 hom. 101 hem.)
• Consequence: ATRX NM_000489.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0330
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-77683789-G-A is Benign according to our data. Variant chrX-77683789-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.033 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

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.1467C>T	p.Thr489Thr	synonymous	Exon 9 of 35	NP_000480.3
	ATRX	NM_138270.5		c.1353C>T	p.Thr451Thr	synonymous	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.1467C>T	p.Thr489Thr	synonymous	Exon 9 of 35	ENSP00000362441.4
	ATRX	ENST00000395603.7	TSL:1	c.1353C>T	p.Thr451Thr	synonymous	Exon 8 of 34	ENSP00000378967.3
	ATRX	ENST00000624166.3	TSL:1	c.1350C>T	p.Thr450Thr	synonymous	Exon 8 of 14	ENSP00000485103.1

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 23 AN: 111624 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000245

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000312 AC: 57 AN: 182887 AF XY: 0.000355

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00294

Gnomad EAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000276 AC: 303 AN: 1095856 Hom.: 0 Cov.: 32 AF XY: 0.000280 AC XY: 101 AN XY: 361336

African (AFR) AF: 0.0000379 AC: 1 AN: 26367

American (AMR) AF: 0.000227 AC: 8 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00212 AC: 41 AN: 19373

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30183

South Asian (SAS) AF: 0.000240 AC: 13 AN: 54084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40422

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4132

European-Non Finnish (NFE) AF: 0.000261 AC: 219 AN: 840073

Other (OTH) AF: 0.000326 AC: 15 AN: 46019

GnomAD4 genome AF: 0.000206 AC: 23 AN: 111679 Hom.: 0 Cov.: 23 AF XY: 0.000206 AC XY: 7 AN XY: 33929

African (AFR) AF: 0.0000974 AC: 3 AN: 30813

American (AMR) AF: 0.000190 AC: 2 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000245 AC: 13 AN: 53008

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.000521 Hom.: 4

Bravo AF: 0.000151

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Alpha thalassemia-X-linked intellectual disability syndrome (1)
-	-	1	ATRX-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.82
DANN	Benign	0.51
PhyloP100		0.033
Mutation Taster		=100/0	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: rs199929884; hg19: chrX-76939281;