Genetic Variant ENST00000398461.5:n.3121+5921G>A (chr14-100851454-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000398461.5(MEG3):n.3121+5921G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,142 control chromosomes in the GnomAD database, including 6,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.26 ( 6034 hom., cov: 32)

Exomes 𝑓: 0.37 ( 14 hom. )

Consequence

MEG3
ENST00000398461.5 intron

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.484

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 14-100851454-G-A is Benign according to our data. Variant chr14-100851454-G-A is described in ClinVar as [Benign]. Clinvar id is 3060854.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
MEG3	NR_046473.1 link	n.6838G>A	non_coding_transcript_exon_variant	Exon 7 of 7
MEG3	NR_190994.1 link	n.6948G>A	non_coding_transcript_exon_variant	Exon 8 of 8
MEG3	NR_190995.1 link	n.7078G>A	non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
MEG3	ENST00000398461.5 link	n.3121+5921G>A	intron_variant	Intron 3 of 3	1
MEG3	ENST00000429159.6 link	n.1275+5921G>A	intron_variant	Intron 6 of 6	1
MEG3	ENST00000451743.6 link	n.1241+5921G>A	intron_variant	Intron 6 of 6	1

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

39878

AN:

151878

Hom.:

6042

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.311

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.329

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.255

GnomAD4 exome

AF:

0.370

AC:

AN:

146

Hom.:

Cov.:

AF XY:

0.385

AC XY:

AN XY:

104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.500

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.500

Gnomad4 FIN exome

AF:

0.500

Gnomad4 NFE exome

AF:

0.371

Gnomad4 OTH exome

AF:

0.500

GnomAD4 genome

AF:

0.262

AC:

39875

AN:

151996

Hom.:

6034

Cov.:

AF XY:

0.265

AC XY:

19676

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.311

Gnomad4 ASJ

AF:

0.319

Gnomad4 EAS

AF:

0.264

Gnomad4 SAS

AF:

0.295

Gnomad4 FIN

AF:

0.329

Gnomad4 NFE

AF:

0.330

Gnomad4 OTH

AF:

0.251

Alfa

AF:

0.310

Hom.:

1874

Bravo

AF:

0.253

Asia WGS

AF:

0.255

AC:

884

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MEG3-related disorder

Benign:1

Jul 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.0

DANN

Benign

0.78

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over