X-77681718-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_000489.6(ATRX):c.3538A>G(p.Ile1180Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,094,107 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 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: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.279

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 -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATRX
• BP4: Computational evidence support a benign effect (MetaRNN=0.08243185).
• BP6: Variant X-77681718-T-C is Benign according to our data. Variant chrX-77681718-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571021.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.3538A>G	p.Ile1180Val	missense_variant	9/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.3538A>G	p.Ile1180Val	missense_variant	9/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000112 AC: 2 AN: 178121 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 63463

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000756

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1094107 Hom.: 0 Cov.: 31 AF XY: 0.00000555 AC XY: 2 AN XY: 360361

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000580

Gnomad4 ASJ exome AF: 0.0000519

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	9.5
Dann	Benign	0.79
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.57	T;.;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.15	N;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.33	T;T;.;.
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.042
MutPred		0.27		Loss of methylation at K1185 (P = 0.1106);.;.;.;
MVP		0.53
MPC		0.022
ClinPred		0.021	T
GERP RS		3.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
gMVP		0.10

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: rs782554626; hg19: chrX-76937210;