rs782778928

chrX-77684343-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000489.6(ATRX):c.913A>G(p.Ser305Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,208,254 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATRX
• BP4: Computational evidence support a benign effect (MetaRNN=0.21380922).
• BP6: Variant X-77684343-T-C is Benign according to our data. Variant chrX-77684343-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533644.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.913A>G	p.Ser305Gly	missense_variant	9/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.913A>G	p.Ser305Gly	missense_variant	9/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 3 AN: 112582 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34730

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 182401 Hom.: 0 AF XY: 0.0000297 AC XY: 2 AN XY: 67271

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 7 AN: 1095620 Hom.: 0 Cov.: 32 AF XY: 0.00000831 AC XY: 3 AN XY: 361106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000833

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000266 AC: 3 AN: 112634 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34792

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2021

The c.913A>G (p.S305G) alteration is located in exon 9 (coding exon 9) of the ATRX gene. This alteration results from a A to G substitution at nucleotide position 913, causing the serine (S) at amino acid position 305 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Alpha thalassemia-X-linked intellectual disability syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	20
Dann	Benign	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.65	T;.;T;T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N;N;.;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;.;D
Polyphen		0.18	B;.;.;.;.
Vest4		0.075
MutPred		0.13		Loss of phosphorylation at S305 (P = 0.0255);.;.;Loss of phosphorylation at S305 (P = 0.0255);.;
MVP		0.85
MPC		0.023
ClinPred		0.15	T
GERP RS		5.5
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs782778928; hg19: chrX-76939835;