Genetic Variant ENST00000424518.6:n.197+566C>T (chr12-53968051-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The ENST00000424518.6(HOTAIR):n.197+566C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.936 in 152,228 control chromosomes in the GnomAD database, including 67,113 homozygotes. 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 0.94 ( 67087 hom., cov: 31)

Exomes 𝑓: 0.98 ( 26 hom. )

Consequence

HOTAIR
ENST00000424518.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

Publications

138 publications found

Variant links:

Genes affected

HOTAIR (HGNC:33510): (HOX transcript antisense RNA) This gene is located within the Homeobox C (HOXC) gene cluster on chromosome 12 and is co-expressed with the HOXC genes. It functions through an RNA product, which binds lysine specific demethylase 1 (LSD1) and Polycomb repressive complex 2 (PRC2), and serves as a scaffold to assemble these regulators at the HOXD gene cluster, thereby promoting epigenetic repression of HOXD. This gene is highly expressed in multiple tumors. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Feb 2019]

HOTAIR links:

ENSG00000274817 (HGNC:):

ENSG00000274817 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000424518.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
HOTAIR	NR_186241.1	MANE Select	n.197+566C>T	intron	N/A
HOTAIR	NR_003716.4		n.55+566C>T	intron	N/A
HOTAIR	NR_047517.2		n.197+566C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
HOTAIR	ENST00000424518.6	TSL:5 MANE Select	n.197+566C>T	intron	N/A
ENSG00000274817	ENST00000616509.1	TSL:6	n.50G>A	non_coding_transcript_exon	Exon 1 of 1
HOTAIR	ENST00000439545.1	TSL:4	n.298+566C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.936

AC:

142314

AN:

152056

Hom.:

67044

Cov.:

show subpopulations

Gnomad AFR

AF:

0.815

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.971

Gnomad ASJ

AF:

0.993

Gnomad EAS

AF:

0.929

Gnomad SAS

AF:

0.938

Gnomad FIN

AF:

0.990

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.989

Gnomad OTH

AF:

0.956

GnomAD4 exome

AF:

0.981

AC:

AN:

Hom.:

Cov.:

AF XY:

0.971

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.936

AC:

142408

AN:

152174

Hom.:

67087

Cov.:

AF XY:

0.936

AC XY:

69658

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.815

AC:

33779

AN:

41472

American (AMR)

AF:

0.971

AC:

14849

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.993

AC:

3446

AN:

3472

East Asian (EAS)

AF:

0.929

AC:

4793

AN:

5158

South Asian (SAS)

AF:

0.938

AC:

4521

AN:

4818

European-Finnish (FIN)

AF:

0.990

AC:

10507

AN:

10608

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.989

AC:

67298

AN:

68034

Other (OTH)

AF:

0.955

AC:

2018

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

421

843

1264

1686

2107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.932

Hom.:

16902

Bravo

AF:

0.931

Asia WGS

AF:

0.940

AC:

3271

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

1.6

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