Genetic Variant MEGF8:p.Val17Leu (chr19-42326292-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001271938.2(MEGF8):c.49G>C(p.Val17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.17

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

MEGF8-related Carpenter syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
Carpenter syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MEGF8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036642343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2 link	c.49G>C	p.Val17Leu	missense_variant	Exon 1 of 42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 link	c.49G>C	p.Val17Leu	missense_variant	Exon 1 of 41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF8	ENST00000251268.11 link	c.49G>C	p.Val17Leu	missense_variant	Exon 1 of 42	5	NM_001271938.2	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8 link	c.49G>C	p.Val17Leu	missense_variant	Exon 1 of 41	1		ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5 link	c.-7037G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 41	5		ENSP00000367313.4	F5GZG7
MEGF8	ENST00000378073.5 link	c.-7037G>C		5_prime_UTR_variant	Exon 1 of 41	5		ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

196808

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1410976

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701932

African (AFR)

AF:

0.00

AC:

AN:

29296

American (AMR)

AF:

0.00

AC:

AN:

32408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24248

East Asian (EAS)

AF:

0.00

AC:

AN:

35432

South Asian (SAS)

AF:

0.00

AC:

AN:

79804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093356

Other (OTH)

AF:

0.00

AC:

AN:

58198

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.49G>C (p.V17L) alteration is located in exon 1 (coding exon 1) of the MEGF8 gene. This alteration results from a G to C substitution at nucleotide position 49, causing the valine (V) at amino acid position 17 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.13

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.072

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.26

N;N

PhyloP100

-1.2

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.018

Sift

Benign

0.72

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0

B;.

Vest4

0.070

MutPred

0.54

Loss of catalytic residue at V17 (P = 0.0408);Loss of catalytic residue at V17 (P = 0.0408);

MVP

0.13

MPC

0.37

ClinPred

0.029

GERP RS

-5.9

Varity_R

0.036

gMVP

0.11

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over