Genetic Variant XIST:n.10511_10521delGATACAGCCAG (chrX-73842202-TCTGGCTGTATC-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6BS2_Supporting

The ENST00000429829.6(XIST):n.10511_10521delGATACAGCCAG variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 512,033 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.00018 ( 0 hom. 28 hem. )

Consequence

XIST
ENST00000429829.6 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.43

Variant links:

Genes affected

XIST (HGNC:12810): (X inactive specific transcript) X inactivation is an early developmental process in mammalian females that transcriptionally silences one of the pair of X chromosomes, thus providing dosage equivalence between males and females. The process is regulated by several factors, including a region of chromosome X called the X inactivation center (XIC). The XIC comprises several non-coding and protein-coding genes, and this gene was the first non-coding gene identified within the XIC. This gene is expressed exclusively from the XIC of the inactive X chromosome, and is essential for the initiation and spread of X-inactivation. The transcript is a spliced RNA. Alternatively spliced transcript variants have been identified, but their full length sequences have not been determined. Mutations in the XIST promoter cause familial skewed X inactivation. [provided by RefSeq, Apr 2012]

XIST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP6

Variant X-73842202-TCTGGCTGTATC-T is Benign according to our data. Variant chrX-73842202-TCTGGCTGTATC-T is described in ClinVar as [Likely_benign]. Clinvar id is 3032664.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
XIST	NR_001564.3 link	n.10502_10512delGATACAGCCAG	non_coding_transcript_exon_variant	Exon 1 of 6
XIST	NR_190997.1 link	n.10502_10512delGATACAGCCAG	non_coding_transcript_exon_variant	Exon 1 of 8
XIST	NR_190999.1 link	n.10502_10512delGATACAGCCAG	non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
XIST	ENST00000429829.6 link	n.10511_10521delGATACAGCCAG	non_coding_transcript_exon_variant	Exon 1 of 6	1
XIST	ENST00000648607.1 link	n.1996_2006delGATACAGCCAG	non_coding_transcript_exon_variant	Exon 1 of 6
XIST	ENST00000648991.1 link	n.1871_1881delGATACAGCCAG	non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111878

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34050

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00491

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.000668

GnomAD3 exomes

AF:

0.000229

AC:

AN:

100617

Hom.:

AF XY:

0.000223

AC XY:

AN XY:

35843

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00384

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:

0.000177

AC:

AN:

400155

Hom.:

AF XY:

0.000190

AC XY:

AN XY:

147599

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00404

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000257

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.000143

AC:

AN:

111878

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34050

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00491

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.000668

Alfa

AF:

0.000695

Hom.:

Bravo

AF:

0.0000982

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

XIST-related disorder

Benign:1

Feb 17, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over