Genetic Variant XIST:n.15919A>G (chrX-73823982-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000429829.6(XIST):n.15919A>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 0.427 in 549,601 control chromosomes in the GnomAD database, including 38,173 homozygotes. There are 84,115 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 0.48 ( 10754 hom., 15388 hem., cov: 22)

Exomes 𝑓: 0.41 ( 27419 hom. 68727 hem. )

Consequence

XIST
ENST00000429829.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.430

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
XIST	NR_001564.3 link	n.15910A>G	non_coding_transcript_exon_variant	Exon 6 of 6
TSIX	NR_003255.2 link	n.31778T>C	non_coding_transcript_exon_variant	Exon 1 of 1
XIST	NR_191000.1 link	n.15701A>G	non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
XIST	ENST00000429829.6 link	n.15919A>G	non_coding_transcript_exon_variant	Exon 6 of 6	1
TSIX	ENST00000604411.1 link	n.31778T>C	non_coding_transcript_exon_variant	Exon 1 of 1	6
XIST	ENST00000648970.1 link	n.5883A>G	non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes

AF:

0.482

AC:

52868

AN:

109750

Hom.:

10749

Cov.:

AF XY:

0.479

AC XY:

15357

AN XY:

32088

show subpopulations

Gnomad AFR

AF:

0.760

Gnomad AMI

AF:

0.179

Gnomad AMR

AF:

0.389

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.944

Gnomad SAS

AF:

0.558

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.295

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.414

GnomAD3 exomes

AF:

0.445

AC:

67947

AN:

152765

Hom.:

11927

AF XY:

0.447

AC XY:

23466

AN XY:

52447

show subpopulations

Gnomad AFR exome

AF:

0.774

Gnomad AMR exome

AF:

0.338

Gnomad ASJ exome

AF:

0.321

Gnomad EAS exome

AF:

0.948

Gnomad SAS exome

AF:

0.569

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.339

Gnomad OTH exome

AF:

0.368

GnomAD4 exome

AF:

0.414

AC:

181933

AN:

439800

Hom.:

27419

Cov.:

AF XY:

0.422

AC XY:

68727

AN XY:

162950

show subpopulations

Gnomad4 AFR exome

AF:

0.757

Gnomad4 AMR exome

AF:

0.343

Gnomad4 ASJ exome

AF:

0.322

Gnomad4 EAS exome

AF:

0.952

Gnomad4 SAS exome

AF:

0.561

Gnomad4 FIN exome

AF:

0.338

Gnomad4 NFE exome

AF:

0.340

Gnomad4 OTH exome

AF:

0.400

GnomAD4 genome

AF:

0.482

AC:

52907

AN:

109801

Hom.:

10754

Cov.:

AF XY:

0.479

AC XY:

15388

AN XY:

32149

show subpopulations

Gnomad4 AFR

AF:

0.760

Gnomad4 AMR

AF:

0.389

Gnomad4 ASJ

AF:

0.321

Gnomad4 EAS

AF:

0.943

Gnomad4 SAS

AF:

0.558

Gnomad4 FIN

AF:

0.309

Gnomad4 NFE

AF:

0.340

Gnomad4 OTH

AF:

0.416

Alfa

AF:

0.387

Hom.:

5893

Bravo

AF:

0.498

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.0

DANN

Benign

0.73

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over