rs1794213

Variant names:

• chrX-73825905-A-C
• rs1794213
• ENST00000429829.7:n.13987T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000429829.7(XIST):​n.13987T>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 0.0978 in 557,191 control chromosomes in the GnomAD database, including 2,015 homozygotes. There are 19,008 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (549 hom., 3473 hem., cov: 23)
  • Exomes 𝑓: 0.095 (1466 hom. 15535 hem.)
• Consequence: XIST ENST00000429829.7 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000429829.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIST	NR_001564.3	MANE Select	n.13987T>G		non_coding_transcript_exon	Exon 6 of 6
	TSIX	NR_003255.2		n.33701A>C		non_coding_transcript_exon	Exon 1 of 1
	XIST	NR_191000.1		n.13778T>G		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIST	ENST00000429829.7	TSL:1 MANE Select	n.13987T>G		non_coding_transcript_exon	Exon 6 of 6
	TSIX	ENST00000604411.1	TSL:6	n.33701A>C		non_coding_transcript_exon	Exon 1 of 1
	XIST	ENST00000648970.1		n.3960T>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.109 AC: 12234 AN: 111857 Hom.: 549 Cov.: 23

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.0498

Gnomad AMR AF: 0.0979

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.00813

Gnomad SAS AF: 0.0687

Gnomad FIN AF: 0.0902

Gnomad MID AF: 0.0542

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0852

GnomAD2 exomes AF: 0.0911 AC: 15036 AN: 165012 AF XY: 0.0879

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0784

Gnomad ASJ exome AF: 0.0607

Gnomad EAS exome AF: 0.00622

Gnomad FIN exome AF: 0.0988

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.0948 AC: 42228 AN: 445278 Hom.: 1466 Cov.: 0 AF XY: 0.0928 AC XY: 15535 AN XY: 167350

African (AFR) AF: 0.136 AC: 1902 AN: 13987

American (AMR) AF: 0.0818 AC: 2810 AN: 34365

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 952 AN: 15411

East Asian (EAS) AF: 0.00291 AC: 79 AN: 27175

South Asian (SAS) AF: 0.0743 AC: 3132 AN: 42138

European-Finnish (FIN) AF: 0.0990 AC: 2820 AN: 28480

Middle Eastern (MID) AF: 0.0640 AC: 194 AN: 3030

European-Non Finnish (NFE) AF: 0.109 AC: 27989 AN: 255871

Other (OTH) AF: 0.0947 AC: 2350 AN: 24821

GnomAD4 genome AF: 0.109 AC: 12249 AN: 111913 Hom.: 549 Cov.: 23 AF XY: 0.102 AC XY: 3473 AN XY: 34089

African (AFR) AF: 0.139 AC: 4278 AN: 30836

American (AMR) AF: 0.0984 AC: 1039 AN: 10564

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 141 AN: 2646

East Asian (EAS) AF: 0.00815 AC: 29 AN: 3559

South Asian (SAS) AF: 0.0693 AC: 185 AN: 2671

European-Finnish (FIN) AF: 0.0902 AC: 546 AN: 6054

Middle Eastern (MID) AF: 0.0594 AC: 13 AN: 219

European-Non Finnish (NFE) AF: 0.110 AC: 5855 AN: 53160

Other (OTH) AF: 0.0848 AC: 129 AN: 1521

Alfa AF: 0.108 Hom.: 3029

Bravo AF: 0.111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.4
DANN	Benign	0.59
PhyloP100		3.3

Splicing

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

Other links and lift over

dbSNP: rs1794213; hg19: chrX-73045740;