ENST00000429829.7:n.17781C>T

Variant names:

• chrX-73822111-G-A
• rs746371115
• ENST00000429829.7:n.17781C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The ENST00000429829.7(XIST):​n.17781C>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 0.000111 in 557,398 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 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 0.00013 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 18 hem.)
• Consequence: XIST ENST00000429829.7 non_coding_transcript_exon
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0520
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-73822111-G-A is Benign according to our data. Variant chrX-73822111-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3048676.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.17781C>T		non_coding_transcript_exon	Exon 6 of 6
	TSIX	NR_003255.2		n.29907G>A		non_coding_transcript_exon	Exon 1 of 1
	XIST	NR_190997.1		n.13883C>T		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIST	ENST00000429829.7	TSL:1 MANE Select	n.17781C>T		non_coding_transcript_exon	Exon 6 of 6
	XIST	ENST00000416330.2	TSL:2	n.491C>T		non_coding_transcript_exon	Exon 3 of 4
	XIST	ENST00000417942.5	TSL:3	n.310C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 15 AN: 112186 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00419

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000413 AC: 68 AN: 164619 AF XY: 0.000402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00518

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 47 AN: 445158 Hom.: 0 Cov.: 0 AF XY: 0.000108 AC XY: 18 AN XY: 167232

African (AFR) AF: 0.00 AC: 0 AN: 13987

American (AMR) AF: 0.00 AC: 0 AN: 34366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15403

East Asian (EAS) AF: 0.00173 AC: 47 AN: 27156

South Asian (SAS) AF: 0.00 AC: 0 AN: 42035

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3030

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 255859

Other (OTH) AF: 0.00 AC: 0 AN: 24823

GnomAD4 genome AF: 0.000134 AC: 15 AN: 112240 Hom.: 0 Cov.: 23 AF XY: 0.000145 AC XY: 5 AN XY: 34418

African (AFR) AF: 0.00 AC: 0 AN: 30952

American (AMR) AF: 0.00 AC: 0 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00421 AC: 15 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6107

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53247

Other (OTH) AF: 0.00 AC: 0 AN: 1535

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000121

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	XIST-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.46
PhyloP100		-0.052

Splicing

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

Other links and lift over

dbSNP: rs746371115; hg19: chrX-73041946;