X-73827076-ATC-A

Variant names:

• chrX-73827076-ATC-A
• rs780559691
• ENST00000429829.6:n.12823_12824delGA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The ENST00000429829.6(XIST):​n.12823_12824delGA 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 0.000368 in 556,386 control chromosomes in the GnomAD database, including 3 homozygotes. There are 61 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (3 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00034 (0 hom. 54 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.754

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant X-73827076-ATC-A is Benign according to our data. Variant chrX-73827076-ATC-A is described in ClinVar as [Likely_benign]. Clinvar id is 3042415.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.12814_12815delGA		non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2	n.34874_34875delCT		non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_190997.1	n.12814_12815delGA		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.12823_12824delGA		non_coding_transcript_exon_variant	Exon 6 of 6	1
XIST	ENST00000421322.3	n.1995_1996delGA		non_coding_transcript_exon_variant	Exon 6 of 7	2
XIST	ENST00000434839.3	n.1525_1526delGA		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes AF: 0.000496 AC: 55 AN: 110881 Hom.: 3 Cov.: 22 AF XY: 0.000211 AC XY: 7 AN XY: 33099

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00241

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00737

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00202

GnomAD3 exomes AF: 0.000531 AC: 88 AN: 165836 Hom.: 0 AF XY: 0.000411 AC XY: 26 AN XY: 63268

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00567

Gnomad SAS exome AF: 0.000371

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000337 AC: 150 AN: 445451 Hom.: 0 AF XY: 0.000322 AC XY: 54 AN XY: 167511

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00316

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000156

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.000496 AC: 55 AN: 110935 Hom.: 3 Cov.: 22 AF XY: 0.000211 AC XY: 7 AN XY: 33161

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00240

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00739

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00199

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000298

Asia WGS AF: 0.00995 AC: 25 AN: 2522

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TSIX-related disorder Benign:1

Jun 26, 2019

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs780559691; hg19: chrX-73046911;