X-73823811-A-T

Variant names:

• chrX-73823811-A-T
• rs73624269
• ENST00000429829.6:n.16090T>A

Variant summary

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

The ENST00000429829.6(XIST):​n.16090T>A 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 0.00134 in 554,731 control chromosomes in the GnomAD database, including 5 homozygotes. There are 207 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., 108 hem., cov: 22)
  • Exomes 𝑓: 0.00073 (1 hom. 99 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.648

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=-0.81).
• BP6: Variant X-73823811-A-T is Benign according to our data. Variant chrX-73823811-A-T is described in ClinVar as [Benign]. Clinvar id is 3045837.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.16081T>A		non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2	n.31607A>T		non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_191000.1	n.15872T>A		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.16090T>A		non_coding_transcript_exon_variant	Exon 6 of 6	1
TSIX	ENST00000604411.1	n.31607A>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
XIST	ENST00000648970.1	n.6054T>A		non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 420 AN: 109422 Hom.: 4 Cov.: 22 AF XY: 0.00335 AC XY: 108 AN XY: 32236

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00202

GnomAD3 exomes AF: 0.00115 AC: 190 AN: 165295 Hom.: 1 AF XY: 0.000874 AC XY: 55 AN XY: 62905

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000728 AC: 324 AN: 445251 Hom.: 1 Cov.: 0 AF XY: 0.000591 AC XY: 99 AN XY: 167381

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000712

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00384 AC: 420 AN: 109480 Hom.: 4 Cov.: 22 AF XY: 0.00334 AC XY: 108 AN XY: 32304

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00115

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00199

Alfa AF: 0.00213 Hom.: 9

Bravo AF: 0.00461

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

XIST-related disorder Benign:1

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.82
DANN	Benign	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs73624269; hg19: chrX-73043646;