X-73842484-G-A

Variant names:

• chrX-73842484-G-A
• rs142303653
• ENST00000429829.6:n.10240C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000429829.6(XIST):​n.10240C>T 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 0.019 in 551,834 control chromosomes in the GnomAD database, including 111 homozygotes. There are 3,575 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 0.016 (20 hom., 552 hem., cov: 23)
  • Exomes 𝑓: 0.020 (91 hom. 3023 hem.)
• Consequence: XIST ENST00000429829.6 non_coding_transcript_exon
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.118

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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-73842484-G-A is Benign according to our data. Variant chrX-73842484-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041442.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0164 (1832/111438) while in subpopulation NFE AF = 0.0244 (1296/53114). AF 95% confidence interval is 0.0233. There are 20 homozygotes in GnomAd4. There are 552 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIST	NR_001564.3	n.10231C>T		non_coding_transcript_exon_variant	Exon 1 of 6
XIST	NR_190997.1	n.10231C>T		non_coding_transcript_exon_variant	Exon 1 of 8
XIST	NR_190999.1	n.10231C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIST	ENST00000429829.6	n.10240C>T		non_coding_transcript_exon_variant	Exon 1 of 6	1
XIST	ENST00000648607.1	n.1725C>T		non_coding_transcript_exon_variant	Exon 1 of 6
XIST	ENST00000648991.1	n.1600C>T		non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 1831 AN: 111391 Hom.: 20 Cov.: 23

Gnomad AFR AF: 0.00320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00835

Gnomad ASJ AF: 0.0125

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00301

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0146

GnomAD2 exomes AF: 0.0158 AC: 2427 AN: 153598 AF XY: 0.0149

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.00554

Gnomad ASJ exome AF: 0.00881

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0540

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0196 AC: 8640 AN: 440396 Hom.: 91 Cov.: 0 AF XY: 0.0185 AC XY: 3023 AN XY: 163290

Gnomad4 AFR exome AF: 0.00345 AC: 48 AN: 13923

Gnomad4 AMR exome AF: 0.00582 AC: 196 AN: 33682

Gnomad4 ASJ exome AF: 0.00947 AC: 145 AN: 15306

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 27040

Gnomad4 SAS exome AF: 0.00585 AC: 241 AN: 41176

Gnomad4 FIN exome AF: 0.0538 AC: 1516 AN: 28186

Gnomad4 NFE exome AF: 0.0239 AC: 6057 AN: 253410

Gnomad4 Remaining exome AF: 0.0174 AC: 429 AN: 24650

GnomAD4 genome AF: 0.0164 AC: 1832 AN: 111438 Hom.: 20 Cov.: 23 AF XY: 0.0164 AC XY: 552 AN XY: 33652

Gnomad4 AFR AF: 0.00319 AC: 0.00319364 AN: 0.00319364

Gnomad4 AMR AF: 0.00834 AC: 0.00833573 AN: 0.00833573

Gnomad4 ASJ AF: 0.0125 AC: 0.0125095 AN: 0.0125095

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00340 AC: 0.00339623 AN: 0.00339623

Gnomad4 FIN AF: 0.0482 AC: 0.0481867 AN: 0.0481867

Gnomad4 NFE AF: 0.0244 AC: 0.0244003 AN: 0.0244003

Gnomad4 OTH AF: 0.0144 AC: 0.0143697 AN: 0.0143697

Alfa AF: 0.0192 Hom.: 155

Bravo AF: 0.0136

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

XIST-related disorder Benign:1

Oct 14, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This 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	-0.88
CADD	Benign	1.3
DANN	Benign	0.39

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs142303653; hg19: chrX-73062319;