X-73823963-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000429829.6(XIST):n.15938A>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 0.00286 in 551,269 control chromosomes in the GnomAD database, including 20 homozygotes. There are 425 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 0.0086 ( 16 hom., 255 hem., cov: 22)

Exomes 𝑓: 0.0014 ( 4 hom. 170 hem. )

Consequence

XIST
ENST00000429829.6 non_coding_transcript_exon

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.856

Variant links:

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]

XIST links:

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]

TSIX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant X-73823963-T-C is Benign according to our data. Variant chrX-73823963-T-C is described in ClinVar as [Benign]. Clinvar id is 3049478.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00861 (959/111354) while in subpopulation AFR AF= 0.0296 (908/30670). AF 95% confidence interval is 0.028. There are 16 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
XIST	NR_001564.3 link	n.15929A>G	non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2 link	n.31759T>C	non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_191000.1 link	n.15720A>G	non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
XIST	ENST00000429829.6 link	n.15938A>G	non_coding_transcript_exon_variant	Exon 6 of 6	1
TSIX	ENST00000604411.1 link	n.31759T>C	non_coding_transcript_exon_variant	Exon 1 of 1	6
XIST	ENST00000648970.1 link	n.5902A>G	non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes

AF:

0.00861

AC:

958

AN:

111305

Hom.:

Cov.:

AF XY:

0.00761

AC XY:

255

AN XY:

33489

show subpopulations

Gnomad AFR

AF:

0.0296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00372

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00664

GnomAD3 exomes

AF:

0.00256

AC:

392

AN:

153006

Hom.:

AF XY:

0.00203

AC XY:

107

AN XY:

52694

show subpopulations

Gnomad AFR exome

AF:

0.0292

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.000988

GnomAD4 exome

AF:

0.00141

AC:

620

AN:

439915

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

170

AN XY:

162777

show subpopulations

Gnomad4 AFR exome

AF:

0.0305

Gnomad4 AMR exome

AF:

0.00273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000242

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.00252

GnomAD4 genome

AF:

0.00861

AC:

959

AN:

111354

Hom.:

Cov.:

AF XY:

0.00760

AC XY:

255

AN XY:

33548

show subpopulations

Gnomad4 AFR

AF:

0.0296

Gnomad4 AMR

AF:

0.00372

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.00655

Alfa

AF:

0.00386

Hom.:

Bravo

AF:

0.00934

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TSIX-related disorder

Benign:1

Aug 09, 2019

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

-0.80

CADD

Benign

7.5

DANN

Benign

0.68

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over