rs761023938

Variant names:

• chrX-73821979-C-T
• rs761023938
• ENST00000429829.7:n.17913G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000429829.7(XIST):​n.17913G>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 0.000129 in 556,383 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 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 0.000080 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00014 (0 hom. 21 hem.)
• Consequence: XIST ENST00000429829.7 non_coding_transcript_exon
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.672
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-73821979-C-T is Benign according to our data. Variant chrX-73821979-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3036287.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 21 XL gene

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.17913G>A		non_coding_transcript_exon	Exon 6 of 6
	TSIX	NR_003255.2		n.29775C>T		non_coding_transcript_exon	Exon 1 of 1
	XIST	NR_191000.1		n.17704G>A		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.17913G>A		non_coding_transcript_exon	Exon 6 of 6
	TSIX	ENST00000604411.1	TSL:6	n.29775C>T		non_coding_transcript_exon	Exon 1 of 1
	XIST	ENST00000648970.1		n.7886G>A		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0000804 AC: 9 AN: 112010 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00265

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000197 AC: 32 AN: 162072 AF XY: 0.000184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.000237

GnomAD4 exome AF: 0.000142 AC: 63 AN: 444373 Hom.: 0 Cov.: 0 AF XY: 0.000126 AC XY: 21 AN XY: 166505

African (AFR) AF: 0.00 AC: 0 AN: 13985

American (AMR) AF: 0.00 AC: 0 AN: 34302

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 46 AN: 15386

East Asian (EAS) AF: 0.00 AC: 0 AN: 27155

South Asian (SAS) AF: 0.0000478 AC: 2 AN: 41858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28441

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3029

European-Non Finnish (NFE) AF: 0.0000470 AC: 12 AN: 255422

Other (OTH) AF: 0.000121 AC: 3 AN: 24795

GnomAD4 genome AF: 0.0000804 AC: 9 AN: 112010 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34230

African (AFR) AF: 0.00 AC: 0 AN: 30751

American (AMR) AF: 0.00 AC: 0 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 7 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53261

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.000738 Hom.: 4

Bravo AF: 0.000102

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.61
PhyloP100		0.67

Splicing

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

Other links and lift over

dbSNP: rs761023938; hg19: chrX-73041814; COSMIC: COSV101351555;