rs397515427

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001271938.2(MEGF8):c.4697G>A(p.Arg1566His) variant causes a missense change. The variant allele was found at a frequency of 0.00000826 in 1,574,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1566C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 6.48

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

PP5

Variant 19-42356848-G-A is Pathogenic according to our data. Variant chr19-42356848-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39845.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.4697G>A	p.Arg1566His	missense_variant	27/42	ENST00000251268.11
MEGF8	NM_001410.3 linkuse as main transcript	c.4496G>A	p.Arg1499His	missense_variant	26/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.4697G>A	p.Arg1566His	missense_variant	27/42	5	NM_001271938.2	A2	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.4496G>A	p.Arg1499His	missense_variant	26/41	1		P2	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-2389G>A		5_prime_UTR_variant	27/41	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000844

AC:

AN:

1422074

Hom.:

Cov.:

AF XY:

0.00000995

AC XY:

AN XY:

703740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.00000915

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MEGF8-related Carpenter syndrome

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Wilkie Group, Clinical Genetics Lab, WIMM, University of Oxford	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.69

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.59

MutPred

0.54

.;Loss of phosphorylation at S1567 (P = 0.1045);

MVP

0.47

MPC

1.3

ClinPred

1.0

GERP RS

5.1

Varity_R

0.78

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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