Variant 19-42368446-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001271938.2(MEGF8):c.6274-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,595,510 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00065 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 2 hom. )

Consequence

MEGF8
NM_001271938.2 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.001318

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.103

Variant links:

Genes affected

MEGF8 (HGNC:3233): (multiple EGF like domains 8) The protein encoded by this gene is a single-pass type I membrane protein of unknown function that contains several EGF-like domains, Kelch repeats, and PSI domains. Defects in this gene are a cause of Carpenter syndrome 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

MEGF8 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=-0.84).

BP6

Variant 19-42368446-C-G is Benign according to our data. Variant chr19-42368446-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435857.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00065 (99/152344) while in subpopulation AFR AF= 0.00115 (48/41586). AF 95% confidence interval is 0.000894. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.6274-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000251268.11
MEGF8	NM_001410.3 linkuse as main transcript	c.6073-9C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.6274-9C>G	splice_polypyrimidine_tract_variant, intron_variant	5	NM_001271938.2	A2	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.6073-9C>G	splice_polypyrimidine_tract_variant, intron_variant	1		P2	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-812-9C>G	splice_polypyrimidine_tract_variant, intron_variant	5
MEGF8	ENST00000598762.1 linkuse as main transcript	c.161+6233C>G	intron_variant	3

Frequencies

GnomAD3 genomes

AF:

0.000650

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000506

AC:

113

AN:

223438

Hom.:

AF XY:

0.000586

AC XY:

AN XY:

122808

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.000473

Gnomad ASJ exome

AF:

0.00201

Gnomad EAS exome

AF:

0.000407

Gnomad SAS exome

AF:

0.000364

Gnomad FIN exome

AF:

0.0000487

Gnomad NFE exome

AF:

0.000444

Gnomad OTH exome

AF:

0.000902

GnomAD4 exome

AF:

0.000385

AC:

556

AN:

1443166

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

297

AN XY:

716862

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.000474

Gnomad4 ASJ exome

AF:

0.00213

Gnomad4 EAS exome

AF:

0.000332

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.0000776

Gnomad4 NFE exome

AF:

0.000271

Gnomad4 OTH exome

AF:

0.000755

GnomAD4 genome

AF:

0.000650

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00115

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000701

Hom.:

Bravo

AF:

0.000676

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 14, 2016

- -

MEGF8-related Carpenter syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.28

DANN

Benign

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0013

dbscSNV1_RF

Benign

0.050

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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