X-73823824-TG-T

Position:

• chrX-73823824-TG-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000429829.6(XIST):​n.16076delC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.044 (265 hom., 1349 hem., cov: 20)
  • Exomes 𝑓: 0.0083 (123 hom. 1216 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.132

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]

TSIX (HGNC:12377): (TSIX transcript, XIST antisense RNA) In mammals, dosage compensation of genes on the X chromosome occurs by X inactivation, which is regulated in cis by the X-inactivation center (XIC) and expression of the XIST non-coding RNA. This gene expresses a non-coding antisense transcript across the 3' end of the XIST locus, and is coexpressed with XIST only from the inactive X chromosome. The mouse ortholog of this locus is required for imprinted X inactivation in extraembryonic tissues and silences Xist through modification of the chromatin structure in the Xist promoter region. In contrast, imprinted X inactivation does not occur in human extraembryonic tissues and transcripts from this locus do not repress XIST expression or affect random X chromosome inactivation in embryonic cells. This transcript is thought to be unspliced and extend over more than 30 kb, but its exact nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-73823824-TG-T is Benign according to our data. Variant chrX-73823824-TG-T is described in ClinVar as [Benign]. Clinvar id is 3038685.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XIST	NR_001564.3	n.16067delC		non_coding_transcript_exon_variant	6/6
TSIX	NR_003255.2	n.31622delG		non_coding_transcript_exon_variant	1/1
XIST	NR_191000.1	n.15858delC		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XIST	ENST00000429829.6	n.16076delC		non_coding_transcript_exon_variant	6/6	1
TSIX	ENST00000604411.1	n.31622delG		non_coding_transcript_exon_variant	1/1	6
XIST	ENST00000648970.1	n.6040delC		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 4870 AN: 111453 Hom.: 265 Cov.: 20 AF XY: 0.0401 AC XY: 1351 AN XY: 33657

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00834

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00750

Gnomad FIN AF: 0.000991

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0141 AC: 2336 AN: 165338 Hom.: 113 AF XY: 0.0116 AC XY: 729 AN XY: 62966

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00616

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00840

GnomAD4 exome AF: 0.00833 AC: 3711 AN: 445283 Hom.: 123 Cov.: 0 AF XY: 0.00726 AC XY: 1216 AN XY: 167411

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00648

Gnomad4 FIN exome AF: 0.000807

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0437 AC: 4868 AN: 111506 Hom.: 265 Cov.: 20 AF XY: 0.0400 AC XY: 1349 AN XY: 33720

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.00834

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00752

Gnomad4 FIN AF: 0.000991

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0228 Hom.: 166

Bravo AF: 0.0509

Asia WGS AF: 0.0160 AC: 41 AN: 2521

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

XIST-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

This variant is classified as 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201836793; hg19: chrX-73043659;