Genetic Variant XIST:n.10104T>C (chrX-73842620-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000429829.6(XIST):n.10104T>C 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 0.0154 in 556,661 control chromosomes in the GnomAD database, including 390 homozygotes. There are 2,565 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 0.044 ( 267 hom., 1353 hem., cov: 22)

Exomes 𝑓: 0.0083 ( 123 hom. 1212 hem. )

Consequence

XIST
ENST00000429829.6 non_coding_transcript_exon

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.221

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant X-73842620-A-G is Benign according to our data. Variant chrX-73842620-A-G is described in ClinVar as [Benign]. Clinvar id is 3039016.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
XIST	NR_001564.3 link	n.10095T>C	non_coding_transcript_exon_variant	Exon 1 of 6
XIST	NR_190997.1 link	n.10095T>C	non_coding_transcript_exon_variant	Exon 1 of 8
XIST	NR_190999.1 link	n.10095T>C	non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
XIST	ENST00000429829.6 link	n.10104T>C	non_coding_transcript_exon_variant	Exon 1 of 6	1
XIST	ENST00000648607.1 link	n.1589T>C	non_coding_transcript_exon_variant	Exon 1 of 6
XIST	ENST00000648991.1 link	n.1464T>C	non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0438

AC:

4887

AN:

111455

Hom.:

267

Cov.:

AF XY:

0.0403

AC XY:

1355

AN XY:

33625

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.00868

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00835

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.0365

GnomAD3 exomes

AF:

0.0140

AC:

2333

AN:

166922

Hom.:

112

AF XY:

0.0115

AC XY:

726

AN XY:

63092

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00932

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00611

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00155

Gnomad OTH exome

AF:

0.00839

GnomAD4 exome

AF:

0.00832

AC:

3703

AN:

445154

Hom.:

123

Cov.:

AF XY:

0.00725

AC XY:

1212

AN XY:

167262

show subpopulations

Gnomad4 AFR exome

AF:

0.152

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.00831

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00647

Gnomad4 FIN exome

AF:

0.000808

Gnomad4 NFE exome

AF:

0.00150

Gnomad4 OTH exome

AF:

0.0145

GnomAD4 genome

AF:

0.0438

AC:

4885

AN:

111507

Hom.:

267

Cov.:

AF XY:

0.0402

AC XY:

1353

AN XY:

33687

show subpopulations

Gnomad4 AFR

AF:

0.147

Gnomad4 AMR

AF:

0.0196

Gnomad4 ASJ

AF:

0.00868

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00837

Gnomad4 FIN

AF:

0.000661

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.0361

Alfa

AF:

0.0173

Hom.:

172

Bravo

AF:

0.0509

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

XIST-related disorder

Benign:1

Jan 20, 2020

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

-0.85

CADD

Benign

0.12

DANN

Benign

0.61

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