chrX-73824521-G-C

Variant summary

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

The ENST00000429829.6(XIST):​n.15380C>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 0.00179 in 554,741 control chromosomes in the GnomAD database, including 2 homozygotes. There are 412 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 0.0012 ( 0 hom., 44 hem., cov: 23)
Exomes 𝑓: 0.0019 ( 2 hom. 368 hem. )

Consequence

XIST
ENST00000429829.6 non_coding_transcript_exon

Scores

2

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.28
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]
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]

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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-73824521-G-C is Benign according to our data. Variant chrX-73824521-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3350445.Status of the report is no_assertion_criteria_provided, 0 stars.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00194 (860/442609) while in subpopulation MID AF= 0.0265 (79/2985). AF 95% confidence interval is 0.0218. There are 2 homozygotes in gnomad4_exome. There are 368 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 44 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XISTNR_001564.3 linkn.15371C>G non_coding_transcript_exon_variant Exon 6 of 6
TSIXNR_003255.2 linkn.32317G>C non_coding_transcript_exon_variant Exon 1 of 1
XISTNR_191000.1 linkn.15162C>G non_coding_transcript_exon_variant Exon 5 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XISTENST00000429829.6 linkn.15380C>G non_coding_transcript_exon_variant Exon 6 of 6 1
TSIXENST00000604411.1 linkn.32317G>C non_coding_transcript_exon_variant Exon 1 of 1 6
XISTENST00000648970.1 linkn.5344C>G non_coding_transcript_exon_variant Exon 7 of 7

Frequencies

GnomAD3 genomes
AF:
0.00120
AC:
134
AN:
112080
Hom.:
0
Cov.:
23
AF XY:
0.00128
AC XY:
44
AN XY:
34258
show subpopulations
Gnomad AFR
AF:
0.0000972
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00254
Gnomad ASJ
AF:
0.00454
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00291
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0168
Gnomad NFE
AF:
0.00136
Gnomad OTH
AF:
0.00536
GnomAD3 exomes
AF:
0.00172
AC:
273
AN:
158465
Hom.:
0
AF XY:
0.00211
AC XY:
120
AN XY:
56915
show subpopulations
Gnomad AFR exome
AF:
0.000281
Gnomad AMR exome
AF:
0.000977
Gnomad ASJ exome
AF:
0.00573
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00371
Gnomad FIN exome
AF:
0.000126
Gnomad NFE exome
AF:
0.00164
Gnomad OTH exome
AF:
0.00460
GnomAD4 exome
AF:
0.00194
AC:
860
AN:
442609
Hom.:
2
Cov.:
0
AF XY:
0.00223
AC XY:
368
AN XY:
165151
show subpopulations
Gnomad4 AFR exome
AF:
0.000502
Gnomad4 AMR exome
AF:
0.000938
Gnomad4 ASJ exome
AF:
0.00619
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00401
Gnomad4 FIN exome
AF:
0.0000706
Gnomad4 NFE exome
AF:
0.00159
Gnomad4 OTH exome
AF:
0.00296
GnomAD4 genome
AF:
0.00119
AC:
133
AN:
112132
Hom.:
0
Cov.:
23
AF XY:
0.00128
AC XY:
44
AN XY:
34320
show subpopulations
Gnomad4 AFR
AF:
0.0000970
Gnomad4 AMR
AF:
0.00254
Gnomad4 ASJ
AF:
0.00454
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00255
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00136
Gnomad4 OTH
AF:
0.00529
Alfa
AF:
0.00239
Hom.:
15
Bravo
AF:
0.00156

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

XIST-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 09, 2024This variant is classified as likely 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
0.28
DANN
Benign
0.64

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.

Other links and lift over

dbSNP: rs201261360; hg19: chrX-73044356; API