Genetic Variant XIST:n.11398-464G>A (chrX-73833838-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000429829.7(XIST):n.11398-464G>A variant causes a intron 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
ENST00000429829.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.11

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
XIST	NR_001564.3	MANE Select	n.11398-464G>A	intron	N/A
XIST	NR_190997.1		n.11398-464G>A	intron	N/A
XIST	NR_190998.1		n.2370-464G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
XIST	ENST00000429829.7	TSL:1 MANE Select	n.11398-464G>A	intron	N/A
XIST	ENST00000421322.3	TSL:2	n.579-464G>A	intron	N/A
XIST	ENST00000434839.3	TSL:5	n.165-464G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0936

AC:

10390

AN:

110985

Hom.:

611

Cov.:

show subpopulations

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.:

AF XY:

0.256

AC XY:

AN XY:

125

show subpopulations

African (AFR)

AF:

0.333

AC:

AN:

American (AMR)

AF:

0.0724

AC:

AN:

304

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0247

AC:

AN:

European-Finnish (FIN)

AF:

0.0227

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0677

AC:

AN:

1314

Other (OTH)

AF:

0.0833

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0936

AC:

10393

AN:

111038

Hom.:

611

Cov.:

AF XY:

0.0853

AC XY:

2839

AN XY:

33286

show subpopulations

African (AFR)

AF:

0.208

AC:

6332

AN:

30430

American (AMR)

AF:

0.0569

AC:

596

AN:

10476

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

308

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3514

South Asian (SAS)

AF:

0.0506

AC:

133

AN:

2629

European-Finnish (FIN)

AF:

0.0126

AC:

AN:

5937

Middle Eastern (MID)

AF:

0.0737

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0528

AC:

2797

AN:

53007

Other (OTH)

AF:

0.0850

AC:

128

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

328

655

983

1310

1638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0741

Hom.:

3827

Bravo

AF:

0.103

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.18

(source)

DANN

Benign

0.074

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over