chrX-73824521-G-C

Variant names:

• chrX-73824521-G-C
• rs201261360
• ENST00000429829.6:n.15380C>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000429829.6(XIST):​n.15380C>G 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 0.00179 in 554,741 control chromosomes in the GnomAD database, including 2 homozygotes. There are 412 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 0.0012 (0 hom., 44 hem., cov: 23)
  • Exomes 𝑓: 0.0019 (2 hom. 368 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.28

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=-0.85).
• BP6: Variant X-73824521-G-C is Benign according to our data. Variant chrX-73824521-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3350445.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00194 (860/442609) while in subpopulation MID AF= 0.0265 (79/2985). AF 95% confidence interval is 0.0218. There are 2 homozygotes in gnomad4_exome. There are 368 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 44 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.15371C>G		non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2	n.32317G>C		non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_191000.1	n.15162C>G		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.15380C>G		non_coding_transcript_exon_variant	Exon 6 of 6	1
TSIX	ENST00000604411.1	n.32317G>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
XIST	ENST00000648970.1	n.5344C>G		non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 134 AN: 112080 Hom.: 0 Cov.: 23 AF XY: 0.00128 AC XY: 44 AN XY: 34258

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00254

Gnomad ASJ AF: 0.00454

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.00136

Gnomad OTH AF: 0.00536

GnomAD3 exomes AF: 0.00172 AC: 273 AN: 158465 Hom.: 0 AF XY: 0.00211 AC XY: 120 AN XY: 56915

Gnomad AFR exome AF: 0.000281

Gnomad AMR exome AF: 0.000977

Gnomad ASJ exome AF: 0.00573

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00371

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00194 AC: 860 AN: 442609 Hom.: 2 Cov.: 0 AF XY: 0.00223 AC XY: 368 AN XY: 165151

Gnomad4 AFR exome AF: 0.000502

Gnomad4 AMR exome AF: 0.000938

Gnomad4 ASJ exome AF: 0.00619

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00401

Gnomad4 FIN exome AF: 0.0000706

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00119 AC: 133 AN: 112132 Hom.: 0 Cov.: 23 AF XY: 0.00128 AC XY: 44 AN XY: 34320

Gnomad4 AFR AF: 0.0000970

Gnomad4 AMR AF: 0.00254

Gnomad4 ASJ AF: 0.00454

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00255

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00136

Gnomad4 OTH AF: 0.00529

Alfa AF: 0.00239 Hom.: 15

Bravo AF: 0.00156

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

XIST-related disorder Benign:1

Sep 09, 2024

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	-0.85
CADD	Benign	0.28
DANN	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201261360; hg19: chrX-73044356;