rs1009948

Positions:

• chrX-73833838-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NR_001564.2(XIST):​n.11437-464G>A variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0932 in 112,963 control chromosomes in the GnomAD database, including 615 homozygotes. There are 2,871 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 0.094 (611 hom., 2839 hem., cov: 22)
  • Exomes 𝑓: 0.068 (4 hom. 32 hem.)
• Consequence: XIST NR_001564.2 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XIST	NR_001564.2	n.11437-464G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIST	ENST00000429829.6	n.11407-464G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0936 AC: 10390 AN: 110985 Hom.: 611 Cov.: 22 AF XY: 0.0853 AC XY: 2834 AN XY: 33223

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0117

Gnomad AMR AF: 0.0571

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0504

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0798

Gnomad NFE AF: 0.0528

Gnomad OTH AF: 0.0860

GnomAD4 exome AF: 0.0681 AC: 131 AN: 1925 Hom.: 4 AF XY: 0.256 AC XY: 32 AN XY: 125

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.0724

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0247

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0677

Gnomad4 OTH exome AF: 0.0833

GnomAD4 genome AF: 0.0936 AC: 10393 AN: 111038 Hom.: 611 Cov.: 22 AF XY: 0.0853 AC XY: 2839 AN XY: 33286

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.0569

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.0528

Gnomad4 OTH AF: 0.0850

Alfa AF: 0.0601 Hom.: 2230

Bravo AF: 0.103

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.074

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1009948; hg19: chrX-73053673;