Variant 19-42376704-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001271938.2(MEGF8):c.8467A>G(p.Ser2823Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 152,318 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.19

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046291947).

BP6

Variant 19-42376704-A-G is Benign according to our data. Variant chr19-42376704-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-42376704-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00462 (704/152318) while in subpopulation AFR AF= 0.016 (666/41572). AF 95% confidence interval is 0.015. There are 8 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.8467A>G	p.Ser2823Gly	missense_variant	42/42	ENST00000251268.11
MEGF8	NM_001410.3 linkuse as main transcript	c.8266A>G	p.Ser2756Gly	missense_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.8467A>G	p.Ser2823Gly	missense_variant	42/42	5	NM_001271938.2	A2	Q7Z7M0-1

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

701

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.00

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00110

AC:

130

AN:

118380

Hom.:

AF XY:

0.00106

AC XY:

AN XY:

62530

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.000892

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000218

Gnomad OTH exome

AF:

0.000281

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000412

AC:

559

AN:

1355198

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

252

AN XY:

663660

show subpopulations

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.000829

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000245

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.00462

AC:

704

AN:

152318

Hom.:

Cov.:

AF XY:

0.00456

AC XY:

340

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0160

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.000550

Hom.:

Bravo

AF:

0.00483

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

MEGF8-related Carpenter syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.2

DANN

Benign

0.94

DEOGEN2

Benign

0.085

.;.;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.67

T;T;T

MetaRNN

Benign

0.0046

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

.;.;N

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.089

Sift

Benign

0.054

T;T;D

Sift4G

Benign

0.11

T;T;D

Polyphen

0.0

B;B;P

Vest4

0.17

MVP

0.18

MPC

0.49

ClinPred

0.0046

GERP RS

2.4

Varity_R

0.046

gMVP

0.34

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