NM_000489.6:c.228G>A

Variant names:

• chrX-77697597-C-T
• rs5959371
• NM_000489.6:c.228G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000489.6(ATRX):​c.228G>A​(p.Ser76Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,208,385 control chromosomes in the GnomAD database, including 233 homozygotes. There are 1,550 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 0.028 (109 hom., 785 hem., cov: 23)
  • Exomes 𝑓: 0.0028 (124 hom. 765 hem.)
• Consequence: ATRX NM_000489.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.77
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant X-77697597-C-T is Benign according to our data. Variant chrX-77697597-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0933 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.228G>A	p.Ser76Ser	synonymous	Exon 4 of 35	NP_000480.3
	ATRX	NM_138270.5		c.228G>A	p.Ser76Ser	synonymous	Exon 4 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.228G>A	p.Ser76Ser	synonymous	Exon 4 of 35	ENSP00000362441.4	P46100-1
	ATRX	ENST00000395603.7	TSL:1	c.228G>A	p.Ser76Ser	synonymous	Exon 4 of 34	ENSP00000378967.3	P46100-4
	ATRX	ENST00000624166.3	TSL:1	c.228G>A	p.Ser76Ser	synonymous	Exon 4 of 14	ENSP00000485103.1	A0A096LNL9

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 3081 AN: 111502 Hom.: 109 Cov.: 23

Gnomad AFR AF: 0.0963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00848

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.0202

GnomAD2 exomes AF: 0.00780 AC: 1425 AN: 182592 AF XY: 0.00425

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.00348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00284 AC: 3113 AN: 1096829 Hom.: 124 Cov.: 29 AF XY: 0.00211 AC XY: 765 AN XY: 362371

African (AFR) AF: 0.0996 AC: 2624 AN: 26351

American (AMR) AF: 0.00438 AC: 154 AN: 35154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30160

South Asian (SAS) AF: 0.000167 AC: 9 AN: 53960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40437

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4130

European-Non Finnish (NFE) AF: 0.0000523 AC: 44 AN: 841252

Other (OTH) AF: 0.00595 AC: 274 AN: 46033

GnomAD4 genome AF: 0.0277 AC: 3086 AN: 111556 Hom.: 109 Cov.: 23 AF XY: 0.0232 AC XY: 785 AN XY: 33806

African (AFR) AF: 0.0962 AC: 2953 AN: 30688

American (AMR) AF: 0.00846 AC: 89 AN: 10514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.000373 AC: 1 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5920

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.000207 AC: 11 AN: 53128

Other (OTH) AF: 0.0199 AC: 30 AN: 1505

Alfa AF: 0.0140 Hom.: 65

Bravo AF: 0.0318

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.35
CADD	Benign	0.15
DANN	Benign	0.51
PhyloP100		-1.8
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: rs5959371; hg19: chrX-76953085; COSMIC: COSV104428679;