X-73821764-T-A

Variant names:

• chrX-73821764-T-A
• rs193140316
• ENST00000429829.6:n.18137A>T

Variant summary

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

The ENST00000429829.6(XIST):​n.18137A>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 0.0019 in 512,145 control chromosomes in the GnomAD database, including 2 homozygotes. There are 329 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 0.0016 (1 hom., 53 hem., cov: 23)
  • Exomes 𝑓: 0.0020 (1 hom. 276 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.963

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]

ENSG00000274655 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-73821764-T-A is Benign according to our data. Variant chrX-73821764-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3038264.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 53 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.18128A>T		non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2	n.29560T>A		non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_191000.1	n.17919A>T		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIST	ENST00000429829.6	n.18137A>T		non_coding_transcript_exon_variant	Exon 6 of 6	1
TSIX	ENST00000604411.1	n.29560T>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
XIST	ENST00000648970.1	n.8101A>T		non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 181 AN: 112423 Hom.: 1 Cov.: 23 AF XY: 0.00153 AC XY: 53 AN XY: 34583

Gnomad AFR AF: 0.000420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00273

Gnomad ASJ AF: 0.00489

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000728

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00661

GnomAD3 exomes AF: 0.00173 AC: 167 AN: 96383 Hom.: 0 AF XY: 0.00158 AC XY: 50 AN XY: 31615

Gnomad AFR exome AF: 0.000356

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00452

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000832

Gnomad FIN exome AF: 0.000436

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00169

GnomAD4 exome AF: 0.00198 AC: 791 AN: 399671 Hom.: 1 Cov.: 0 AF XY: 0.00189 AC XY: 276 AN XY: 145745

Gnomad4 AFR exome AF: 0.000651

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00456

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000798

Gnomad4 FIN exome AF: 0.000466

Gnomad4 NFE exome AF: 0.00232

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00161 AC: 181 AN: 112474 Hom.: 1 Cov.: 23 AF XY: 0.00153 AC XY: 53 AN XY: 34644

Gnomad4 AFR AF: 0.000419

Gnomad4 AMR AF: 0.00273

Gnomad4 ASJ AF: 0.00489

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000730

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.00652

Alfa AF: 0.00255 Hom.: 19

Bravo AF: 0.00206

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

XIST-related disorder Benign:1

Mar 16, 2021

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	-0.88
CADD	Benign	0.15
DANN	Benign	0.26

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193140316; hg19: chrX-73041599; COSMIC: COSV68904282;