NM_000489.6:c.2169G>C

Variant names:

• chrX-77683087-C-G
• rs61752456
• NM_000489.6:c.2169G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000489.6(ATRX):​c.2169G>C​(p.Glu723Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,208,785 control chromosomes in the GnomAD database, including 2 homozygotes. There are 214 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E723V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., 15 hem., cov: 22)
  • Exomes 𝑓: 0.00054 (1 hom. 199 hem.)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.338
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05140379).
• BP6: Variant X-77683087-C-G is Benign according to our data. Variant chrX-77683087-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000413 (46/111470) while in subpopulation NFE AF = 0.000754 (40/53023). AF 95% confidence interval is 0.000569. There are 1 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 15 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.2169G>C	p.Glu723Asp	missense	Exon 9 of 35	NP_000480.3
	ATRX	NM_138270.5		c.2055G>C	p.Glu685Asp	missense	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.2169G>C	p.Glu723Asp	missense	Exon 9 of 35	ENSP00000362441.4
	ATRX	ENST00000395603.7	TSL:1	c.2055G>C	p.Glu685Asp	missense	Exon 8 of 34	ENSP00000378967.3
	ATRX	ENST00000624166.3	TSL:1	c.1965G>C	p.Glu655Asp	missense	Exon 9 of 14	ENSP00000485103.1

Frequencies

GnomAD3 genomes AF: 0.000413 AC: 46 AN: 111415 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.0000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000754

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000236 AC: 43 AN: 182526 AF XY: 0.000253

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000537 AC: 589 AN: 1097315 Hom.: 1 Cov.: 33 AF XY: 0.000549 AC XY: 199 AN XY: 362801

African (AFR) AF: 0.0000758 AC: 2 AN: 26381

American (AMR) AF: 0.0000568 AC: 2 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.000826 AC: 16 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54130

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40267

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.000656 AC: 552 AN: 841553

Other (OTH) AF: 0.000282 AC: 13 AN: 46075

GnomAD4 genome AF: 0.000413 AC: 46 AN: 111470 Hom.: 1 Cov.: 22 AF XY: 0.000445 AC XY: 15 AN XY: 33680

African (AFR) AF: 0.0000650 AC: 2 AN: 30783

American (AMR) AF: 0.00 AC: 0 AN: 10435

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2662

European-Finnish (FIN) AF: 0.000168 AC: 1 AN: 5952

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

European-Non Finnish (NFE) AF: 0.000754 AC: 40 AN: 53023

Other (OTH) AF: 0.00 AC: 0 AN: 1522

Alfa AF: 0.000711 Hom.: 17

Bravo AF: 0.000363

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.00104

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	Alpha thalassemia-X-linked intellectual disability syndrome (1)
-	-	1	ATRX-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.0087	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.65	T
PhyloP100		0.34
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.20
Sift	Benign	0.35	T
Sift4G	Benign	0.76	T
Polyphen		0.0020	B
Vest4		0.058
MutPred		0.092		Loss of methylation at K720 (P = 0.1105)
MVP		0.40
MPC		0.023
ClinPred		0.011	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.049
Mutation Taster		=99/1	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: rs61752456; hg19: chrX-76938579;