X-73827734-C-T

Variant names:

• chrX-73827734-C-T
• rs73486505
• ENST00000429829.6:n.12167G>A

Variant summary

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

The ENST00000429829.6(XIST):​n.12167G>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 0.0155 in 546,311 control chromosomes in the GnomAD database, including 387 homozygotes. There are 2,508 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 0.044 (266 hom., 1350 hem., cov: 23)
  • Exomes 𝑓: 0.0083 (121 hom. 1158 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.423

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=-0.62).
• BP6: Variant X-73827734-C-T is Benign according to our data. Variant chrX-73827734-C-T is described in ClinVar as [Benign]. Clinvar id is 3039573.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.12158G>A		non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2	n.35530C>T		non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_190997.1	n.12158G>A		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.12167G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1
XIST	ENST00000421322.3	n.1339G>A		non_coding_transcript_exon_variant	Exon 6 of 7	2
XIST	ENST00000433732.2	n.450G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 4873 AN: 110487 Hom.: 266 Cov.: 23 AF XY: 0.0411 AC XY: 1352 AN XY: 32857

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.00834

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00814

Gnomad FIN AF: 0.00120

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.00127

Gnomad OTH AF: 0.0364

GnomAD3 exomes AF: 0.0133 AC: 1931 AN: 144850 Hom.: 94 AF XY: 0.0103 AC XY: 492 AN XY: 47740

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00931

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00604

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00839

GnomAD4 exome AF: 0.00828 AC: 3607 AN: 435771 Hom.: 121 Cov.: 0 AF XY: 0.00722 AC XY: 1158 AN XY: 160451

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.00819

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00651

Gnomad4 FIN exome AF: 0.000787

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0441 AC: 4871 AN: 110540 Hom.: 266 Cov.: 23 AF XY: 0.0410 AC XY: 1350 AN XY: 32920

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.00834

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00816

Gnomad4 FIN AF: 0.00120

Gnomad4 NFE AF: 0.00127

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0226 Hom.: 167

Bravo AF: 0.0509

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

XIST-related disorder Benign:1

Jan 20, 2020

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	-0.62
CADD	Benign	6.3
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs73486505; hg19: chrX-73047569;