Genetic Variant ENST00000649261.2:n.1643+6488G>A (chr14-100852021-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000649261.2(MEG3):n.1643+6488G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 235,934 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.011 ( 31 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

MEG3
ENST00000649261.2 intron

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.90

Publications

1 publications found

Variant links:

Genes affected

MEG3 (HGNC:14575): (maternally expressed 3) This gene is a maternally expressed imprinted gene. Multiple alternatively spliced transcript variants have been transcribed from this gene and all of them are long non-coding RNAs (lncRNAs). This gene is expressed in many normal tissues, but its expression is lost in multiple cancer cell lines of various tissue origins. It inhibits tumor cell proliferation in vitro. It also interacts with the tumor suppressor p53, and regulates p53 target gene expression. Its deletion enhances angiogenesis in vivo. Many experimental evidences demonstrate that this gene is a lncRNA tumor suppressor. [provided by RefSeq, Mar 2012]

MEG3 links:

ENSG00000258663 (HGNC:):

ENSG00000258663 links:

MIR493HG (HGNC:55978): (MIR493 cluster host gene)

MIR493HG links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 14-100852021-G-A is Benign according to our data. Variant chr14-100852021-G-A is described in ClinVar as Benign. ClinVar VariationId is 3045679.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1721/152248) while in subpopulation AFR AF = 0.0391 (1624/41532). AF 95% confidence interval is 0.0375. There are 31 homozygotes in GnomAd4. There are 803 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649261.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
MEG3	NR_190993.1	MANE Select	n.1643+6488G>A	intron	N/A
MEG3	NR_046473.1		n.7405G>A	non_coding_transcript_exon	Exon 7 of 7
MEG3	NR_190994.1		n.7515G>A	non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
MEG3	ENST00000649261.2	MANE Select	n.1643+6488G>A	intron	N/A
MEG3	ENST00000398461.6	TSL:1	n.3121+6488G>A	intron	N/A
MEG3	ENST00000429159.7	TSL:1	n.1275+6488G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1711

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00718

GnomAD4 exome

AF:

0.00110

AC:

AN:

83686

Hom.:

Cov.:

AF XY:

0.000814

AC XY:

AN XY:

45462

show subpopulations

African (AFR)

AF:

0.0358

AC:

AN:

1870

American (AMR)

AF:

0.00196

AC:

AN:

4582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1708

East Asian (EAS)

AF:

0.00

AC:

AN:

2680

South Asian (SAS)

AF:

0.000121

AC:

AN:

16564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3898

Middle Eastern (MID)

AF:

0.00309

AC:

AN:

324

European-Non Finnish (NFE)

AF:

0.0000835

AC:

AN:

47898

Other (OTH)

AF:

0.00216

AC:

AN:

4162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0113

AC:

1721

AN:

152248

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

803

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0391

AC:

1624

AN:

41532

American (AMR)

AF:

0.00484

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68032

Other (OTH)

AF:

0.00711

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

173

259

346

432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00253

Hom.:

Bravo

AF:

0.0134

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MEG3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

1.9

Mutation Taster

=100/0

polymorphism

(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