Genetic Variant XIST:n.6120A>G (chrX-73846604-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.6120A>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 0.24 in 556,275 control chromosomes in the GnomAD database, including 16,192 homozygotes. There are 50,649 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 0.19 ( 2207 hom., 6636 hem., cov: 23)

Exomes 𝑓: 0.25 ( 13985 hom. 44013 hem. )

Consequence

XIST
ENST00000429829.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.640

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:

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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=-0.86).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
XIST	NR_001564.3 link	n.6111A>G	non_coding_transcript_exon_variant	Exon 1 of 6
XIST	NR_190997.1 link	n.6111A>G	non_coding_transcript_exon_variant	Exon 1 of 8
XIST	NR_190999.1 link	n.6111A>G	non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
XIST	ENST00000429829.6 link	n.6120A>G	non_coding_transcript_exon_variant	Exon 1 of 6	1
XIST	ENST00000650186.1 link	n.397A>G	non_coding_transcript_exon_variant	Exon 1 of 7
XIST	ENST00000650627.1 link	n.4989A>G	non_coding_transcript_exon_variant	Exon 1 of 8

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

21270

AN:

110879

Hom.:

2210

Cov.:

AF XY:

0.200

AC XY:

6631

AN XY:

33155

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.935

Gnomad SAS

AF:

0.429

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.137

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.170

GnomAD3 exomes

AF:

0.269

AC:

45038

AN:

167372

Hom.:

6220

AF XY:

0.277

AC XY:

17582

AN XY:

63496

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.215

Gnomad ASJ exome

AF:

0.149

Gnomad EAS exome

AF:

0.942

Gnomad SAS exome

AF:

0.430

Gnomad FIN exome

AF:

0.214

Gnomad NFE exome

AF:

0.175

Gnomad OTH exome

AF:

0.220

GnomAD4 exome

AF:

0.252

AC:

112011

AN:

445344

Hom.:

13985

Cov.:

AF XY:

0.263

AC XY:

44013

AN XY:

167392

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.212

Gnomad4 ASJ exome

AF:

0.150

Gnomad4 EAS exome

AF:

0.949

Gnomad4 SAS exome

AF:

0.422

Gnomad4 FIN exome

AF:

0.218

Gnomad4 NFE exome

AF:

0.177

Gnomad4 OTH exome

AF:

0.213

GnomAD4 genome

AF:

0.192

AC:

21276

AN:

110931

Hom.:

2207

Cov.:

AF XY:

0.200

AC XY:

6636

AN XY:

33217

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.194

Gnomad4 ASJ

AF:

0.152

Gnomad4 EAS

AF:

0.934

Gnomad4 SAS

AF:

0.428

Gnomad4 FIN

AF:

0.205

Gnomad4 NFE

AF:

0.174

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.176

Hom.:

2160

Bravo

AF:

0.191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.77

DANN

Benign

0.81

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