X-73827109-G-A

Variant names:

• chrX-73827109-G-A
• rs200052369
• ENST00000429829.6:n.12792C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000429829.6(XIST):​n.12792C>T 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 0.00169 in 556,513 control chromosomes in the GnomAD database, including 1 homozygotes. There are 394 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 50 hem., cov: 22)
  • Exomes 𝑓: 0.0017 (1 hom. 344 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.353

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-73827109-G-A is Benign according to our data. Variant chrX-73827109-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3042582.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 50 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.12783C>T		non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2	n.34905G>A		non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_190997.1	n.12783C>T		non_coding_transcript_exon_variant	Exon 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIST	ENST00000429829.6	n.12792C>T		non_coding_transcript_exon_variant	Exon 6 of 6	1
XIST	ENST00000421322.3	n.1964C>T		non_coding_transcript_exon_variant	Exon 6 of 7	2
XIST	ENST00000434839.3	n.1494C>T		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 168 AN: 111011 Hom.: 0 Cov.: 22 AF XY: 0.00151 AC XY: 50 AN XY: 33201

Gnomad AFR AF: 0.000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.00118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00202

GnomAD3 exomes AF: 0.00136 AC: 225 AN: 165846 Hom.: 0 AF XY: 0.00153 AC XY: 97 AN XY: 63276

Gnomad AFR exome AF: 0.000180

Gnomad AMR exome AF: 0.000478

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.00191

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00173 AC: 771 AN: 445451 Hom.: 1 Cov.: 0 AF XY: 0.00205 AC XY: 344 AN XY: 167509

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000523

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00151 AC: 168 AN: 111062 Hom.: 0 Cov.: 22 AF XY: 0.00150 AC XY: 50 AN XY: 33262

Gnomad4 AFR AF: 0.000328

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00115

Gnomad4 FIN AF: 0.00118

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00200

Alfa AF: 0.00189 Hom.: 12

Bravo AF: 0.00122

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TSIX-related disorder Benign:1

May 16, 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
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.0
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200052369; hg19: chrX-73046944;