rs148975763

Variant names:

• chrX-77635979-G-T
• rs148975763
• NM_000489.6:c.4635C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-77635979-G-T
• chrX-77635979-G-A
• chrX-77635979-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000489.6(ATRX):​c.4635C>A​(p.Thr1545Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 1,206,259 control chromosomes in the GnomAD database, including 5 homozygotes. There are 195 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., 103 hem., cov: 22)
  • Exomes 𝑓: 0.00033 (4 hom. 92 hem.)
• Consequence: ATRX NM_000489.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.213
• Publications: 2 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=-0.45).
• BP6: Variant X-77635979-G-T is Benign according to our data. Variant chrX-77635979-G-T is described in ClinVar as Benign. ClinVar VariationId is 93138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.213 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00328 (368/112202) while in subpopulation AFR AF = 0.0114 (351/30909). AF 95% confidence interval is 0.0104. There are 1 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 103 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	NM_000489.6	MANE Select	c.4635C>A	p.Thr1545Thr	synonymous	Exon 16 of 35	NP_000480.3
	ATRX	NM_138270.5		c.4521C>A	p.Thr1507Thr	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.4635C>A	p.Thr1545Thr	synonymous	Exon 16 of 35	ENSP00000362441.4	P46100-1
	ATRX	ENST00000395603.7	TSL:1	c.4521C>A	p.Thr1507Thr	synonymous	Exon 15 of 34	ENSP00000378967.3	P46100-4
	ATRX	ENST00000480283.5	TSL:1	n.*4263C>A		non_coding_transcript_exon	Exon 17 of 36	ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 368 AN: 112148 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000846

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.000919 AC: 167 AN: 181704 AF XY: 0.000588

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000331 AC: 362 AN: 1094057 Hom.: 4 Cov.: 29 AF XY: 0.000256 AC XY: 92 AN XY: 359723

African (AFR) AF: 0.0118 AC: 311 AN: 26307

American (AMR) AF: 0.000540 AC: 19 AN: 35166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19320

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40505

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3860

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 838889

Other (OTH) AF: 0.000609 AC: 28 AN: 45941

GnomAD4 genome AF: 0.00328 AC: 368 AN: 112202 Hom.: 1 Cov.: 22 AF XY: 0.00300 AC XY: 103 AN XY: 34388

African (AFR) AF: 0.0114 AC: 351 AN: 30909

American (AMR) AF: 0.000845 AC: 9 AN: 10651

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3585

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53203

Other (OTH) AF: 0.00195 AC: 3 AN: 1536

Alfa AF: 0.00174 Hom.: 6

Bravo AF: 0.00391

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alpha thalassemia-X-linked intellectual disability syndrome (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.4
DANN	Benign	0.66
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs148975763; hg19: chrX-76891470;