chrX-73823462-G-A

Variant names:

• chrX-73823462-G-A
• rs138595829
• ENST00000429829.6:n.16439C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000429829.6(XIST):​n.16439C>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 0.0126 in 514,253 control chromosomes in the GnomAD database, including 317 homozygotes. There are 1,674 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 0.039 (239 hom., 1080 hem., cov: 22)
  • Exomes 𝑓: 0.0055 (78 hom. 594 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.321

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant X-73823462-G-A is Benign according to our data. Variant chrX-73823462-G-A is described in ClinVar as [Benign]. Clinvar id is 3041924.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.16430C>T		non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2	n.31258G>A		non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_191000.1	n.16221C>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.16439C>T		non_coding_transcript_exon_variant	Exon 6 of 6	1
TSIX	ENST00000604411.1	n.31258G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
XIST	ENST00000648970.1	n.6403C>T		non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 4267 AN: 110511 Hom.: 239 Cov.: 22 AF XY: 0.0329 AC XY: 1077 AN XY: 32723

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000384

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00426

Gnomad NFE AF: 0.000359

Gnomad OTH AF: 0.0324

GnomAD3 exomes AF: 0.00895 AC: 875 AN: 97779 Hom.: 26 AF XY: 0.00647 AC XY: 229 AN XY: 35415

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.00762

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000348

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00554 AC: 2235 AN: 403699 Hom.: 78 Cov.: 0 AF XY: 0.00397 AC XY: 594 AN XY: 149471

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.00836

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.0386 AC: 4268 AN: 110554 Hom.: 239 Cov.: 22 AF XY: 0.0330 AC XY: 1080 AN XY: 32776

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000385

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000359

Gnomad4 OTH AF: 0.0320

Alfa AF: 0.0206 Hom.: 100

Bravo AF: 0.0453

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TSIX-related disorder Benign:1

Feb 24, 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	-0.96
CADD	Benign	2.4
DANN	Benign	0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs138595829; hg19: chrX-73043297;