rs147216997

Positions:

chr19-42375910-C-T

Variant summary

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

The NM_001271938.2(MEGF8):c.7673C>T(p.Pro2558Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 1,599,210 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0062 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 38 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.302

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:

MEGF8 (HGNC:):

MEGF8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047466457).

BP6

Variant 19-42375910-C-T is Benign according to our data. Variant chr19-42375910-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr19-42375910-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00615 (937/152302) while in subpopulation NFE AF= 0.01 (681/68012). AF 95% confidence interval is 0.00939. There are 7 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.7673C>T	p.Pro2558Leu	missense_variant	42/42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 linkuse as main transcript	c.7472C>T	p.Pro2491Leu	missense_variant	41/41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.7673C>T	p.Pro2558Leu	missense_variant	42/42	5	NM_001271938.2	ENSP00000251268.5		Q7Z7M0-1

Frequencies

GnomAD3 genomes

AF:

0.00616

AC:

937

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00576

AC:

1333

AN:

231274

Hom.:

AF XY:

0.00591

AC XY:

751

AN XY:

127128

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00299

Gnomad ASJ exome

AF:

0.00197

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00332

Gnomad FIN exome

AF:

0.00860

Gnomad NFE exome

AF:

0.00867

Gnomad OTH exome

AF:

0.00644

GnomAD4 exome

AF:

0.00766

AC:

11085

AN:

1446908

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

5396

AN XY:

718180

show subpopulations

Gnomad4 AFR exome

AF:

0.00150

Gnomad4 AMR exome

AF:

0.00290

Gnomad4 ASJ exome

AF:

0.00206

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.00286

Gnomad4 FIN exome

AF:

0.00887

Gnomad4 NFE exome

AF:

0.00879

Gnomad4 OTH exome

AF:

0.00618

GnomAD4 genome

AF:

0.00615

AC:

937

AN:

152302

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

412

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00385

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00828

Gnomad4 NFE

AF:

0.0100

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00716

Hom.:

Bravo

AF:

0.00506

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00208

AC:

ESP6500EA

AF:

0.00696

AC:

ExAC

AF:

0.00569

AC:

685

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MEGF8: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 16, 2016	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.7472C>T (p.P2491L) alteration is located in exon 41 (coding exon 41) of the MEGF8 gene. This alteration results from a C to T substitution at nucleotide position 7472, causing the proline (P) at amino acid position 2491 to be replaced by a leucine (L). 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 29, 2024

- -

MEGF8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

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

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.2

DANN

Benign

0.43

DEOGEN2

Benign

0.096

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

.;.;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.043

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.083

T;D;T

Polyphen

0.0030

B;B;B

Vest4

0.17

MVP

0.043

MPC

0.55

ClinPred

0.0039

GERP RS

0.090

Varity_R

0.037

gMVP

0.37

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