19-42358892-C-G

Position:

chr19-42358892-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001271938.2(MEGF8):c.5281C>G(p.Leu1761Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,611,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00044 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.473

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019727409).

BP6

Variant 19-42358892-C-G is Benign according to our data. Variant chr19-42358892-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000441 (67/151960) while in subpopulation NFE AF= 0.000941 (64/67990). AF 95% confidence interval is 0.000756. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.5281C>G	p.Leu1761Val	missense_variant	30/42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3 linkuse as main transcript	c.5080C>G	p.Leu1694Val	missense_variant	29/41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.5281C>G	p.Leu1761Val	missense_variant	30/42	5	NM_001271938.2	ENSP00000251268	A2	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.5080C>G	p.Leu1694Val	missense_variant	29/41	1		ENSP00000334219	P2	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-1805C>G		5_prime_UTR_variant	30/41	5		ENSP00000367313

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

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:

0.000941

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000463

AC:

114

AN:

246420

Hom.:

AF XY:

0.000465

AC XY:

AN XY:

133356

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000908

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000597

AC:

872

AN:

1459598

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

462

AN XY:

725806

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.000394

Gnomad4 NFE exome

AF:

0.000734

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000441

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.0000484

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:

0.000941

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000539

Hom.:

Bravo

AF:

0.000393

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000577

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.5080C>G (p.L1694V) alteration is located in exon 29 (coding exon 29) of the MEGF8 gene. This alteration results from a C to G substitution at nucleotide position 5080, causing the leucine (L) at amino acid position 1694 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MEGF8-related Carpenter syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.10

DANN

Benign

0.25

DEOGEN2

Benign

0.070

.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.0010

Sift

Benign

0.17

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.0

B;B

Vest4

0.12

MVP

0.12

MPC

0.033

ClinPred

0.022

GERP RS

-5.1

Varity_R

0.034

gMVP

0.23

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

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