X-73823982-T-C

Variant names:

• chrX-73823982-T-C
• rs1620574
• ENST00000429829.7:n.15910A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000429829.7(XIST):​n.15910A>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 0.427 in 549,601 control chromosomes in the GnomAD database, including 38,173 homozygotes. There are 84,115 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 0.48 (10754 hom., 15388 hem., cov: 22)
  • Exomes 𝑓: 0.41 (27419 hom. 68727 hem.)
• Consequence: XIST ENST00000429829.7 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.430
• Publications: 13 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000429829.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIST	NR_001564.3	MANE Select	n.15910A>G		non_coding_transcript_exon	Exon 6 of 6
	TSIX	NR_003255.2		n.31778T>C		non_coding_transcript_exon	Exon 1 of 1
	XIST	NR_191000.1		n.15701A>G		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIST	ENST00000429829.7	TSL:1 MANE Select	n.15910A>G		non_coding_transcript_exon	Exon 6 of 6
	TSIX	ENST00000604411.1	TSL:6	n.31778T>C		non_coding_transcript_exon	Exon 1 of 1
	XIST	ENST00000648970.1		n.5883A>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.482 AC: 52868 AN: 109750 Hom.: 10749 Cov.: 22

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.414

GnomAD2 exomes AF: 0.445 AC: 67947 AN: 152765 AF XY: 0.447

Gnomad AFR exome AF: 0.774

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.948

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.414 AC: 181933 AN: 439800 Hom.: 27419 Cov.: 0 AF XY: 0.422 AC XY: 68727 AN XY: 162950

African (AFR) AF: 0.757 AC: 10541 AN: 13932

American (AMR) AF: 0.343 AC: 11545 AN: 33699

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 4929 AN: 15290

East Asian (EAS) AF: 0.952 AC: 25769 AN: 27068

South Asian (SAS) AF: 0.561 AC: 23282 AN: 41530

European-Finnish (FIN) AF: 0.338 AC: 9507 AN: 28165

Middle Eastern (MID) AF: 0.252 AC: 758 AN: 3006

European-Non Finnish (NFE) AF: 0.340 AC: 85767 AN: 252545

Other (OTH) AF: 0.400 AC: 9835 AN: 24565

GnomAD4 genome AF: 0.482 AC: 52907 AN: 109801 Hom.: 10754 Cov.: 22 AF XY: 0.479 AC XY: 15388 AN XY: 32149

African (AFR) AF: 0.760 AC: 22902 AN: 30149

American (AMR) AF: 0.389 AC: 4020 AN: 10334

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 839 AN: 2615

East Asian (EAS) AF: 0.943 AC: 3250 AN: 3445

South Asian (SAS) AF: 0.558 AC: 1412 AN: 2532

European-Finnish (FIN) AF: 0.309 AC: 1813 AN: 5859

Middle Eastern (MID) AF: 0.306 AC: 66 AN: 216

European-Non Finnish (NFE) AF: 0.340 AC: 17860 AN: 52475

Other (OTH) AF: 0.416 AC: 624 AN: 1499

Alfa AF: 0.387 Hom.: 5893

Bravo AF: 0.498

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.73
PhyloP100		0.43

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1620574;

hg19: chrX-73043817;