19-42351670-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001271938.2(MEGF8):c.3010C>T(p.Arg1004Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,590,272 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1004Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.14

Publications

0 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.108997494).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000795 (121/152282) while in subpopulation NFE AF = 0.00144 (98/68002). AF 95% confidence interval is 0.00121. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2 link	c.3010C>T	p.Arg1004Trp	missense_variant	Exon 18 of 42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 link	c.2809C>T	p.Arg937Trp	missense_variant	Exon 17 of 41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF8	ENST00000251268.11 link	c.3010C>T	p.Arg1004Trp	missense_variant	Exon 18 of 42	5	NM_001271938.2	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8 link	c.2809C>T	p.Arg937Trp	missense_variant	Exon 17 of 41	1		ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5 link	c.-4076C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 18 of 41	5		ENSP00000367313.4	F5GZG7
MEGF8	ENST00000378073.5 link	c.-4076C>T		5_prime_UTR_variant	Exon 18 of 41	5		ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000559

AC:

118

AN:

211216

AF XY:

0.000526

show subpopulations

Gnomad AFR exome

AF:

0.000557

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00107

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000527

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00122

AC:

1753

AN:

1437990

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

842

AN XY:

713272

show subpopulations

African (AFR)

AF:

0.000274

AC:

AN:

32884

American (AMR)

AF:

0.0000978

AC:

AN:

40920

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

38182

South Asian (SAS)

AF:

0.0000364

AC:

AN:

82484

European-Finnish (FIN)

AF:

0.0000971

AC:

AN:

51468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00150

AC:

1657

AN:

1101186

Other (OTH)

AF:

0.000740

AC:

AN:

59426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

100

200

299

399

499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152282

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41568

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00144

AC:

AN:

68002

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000676

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000438

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MEGF8-related Carpenter syndrome

Uncertain:3

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 937 of the MEGF8 protein (p.Arg937Trp). This variant is present in population databases (rs141383715, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MEGF8-related conditions. ClinVar contains an entry for this variant (Variation ID: 546842). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2809C>T (p.R937W) alteration is located in exon 17 (coding exon 17) of the MEGF8 gene. This alteration results from a C to T substitution at nucleotide position 2809, causing the arginine (R) at amino acid position 937 to be replaced by a tryptophan (W). 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

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

.;D

Eigen

Benign

-0.062

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L

PhyloP100

1.1

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.1

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.46

MVP

0.043

MPC

1.0

ClinPred

0.12

GERP RS

-0.25

Varity_R

0.22

gMVP

0.56

Mutation Taster

=74/26

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over