rs782162927

chrX-77682641-T-AchrX-77682641-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_000489.6(ATRX):c.2615A>T(p.Gln872Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q872Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.377

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ATRX
• BP4: Computational evidence support a benign effect (MetaRNN=0.12188569).
• BP6: Variant X-77682641-T-A is Benign according to our data. Variant chrX-77682641-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 580349.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.2615A>T	p.Gln872Leu	missense_variant	9/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.2615A>T	p.Gln872Leu	missense_variant	9/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000552 AC: 1 AN: 181242 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66532

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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

Jan 17, 2024

The c.2615A>T (p.Q872L) alteration is located in exon 9 (coding exon 9) of the ATRX gene. This alteration results from a A to T substitution at nucleotide position 2615, causing the glutamine (Q) at amino acid position 872 to be replaced by a leucine (L). 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

Sep 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	12
Dann	Benign	0.58
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.78	T;.;T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N;N;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;D;.;.
Sift4G	Benign	0.30	T;T;T;.
Polyphen		0.0010	B;.;.;.
Vest4		0.28
MutPred		0.19		Gain of sheet (P = 0.0477);.;.;.;
MVP		0.69
MPC		0.024
ClinPred		0.092	T
GERP RS		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.28

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: rs782162927; hg19: chrX-76938133;