rs139192223

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001271938.2(MEGF8):c.7567A>G(p.Thr2523Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,612,540 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 2 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.529

Publications

8 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058243275).

BP6

Variant 19-42375804-A-G is Benign according to our data. Variant chr19-42375804-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 565484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00075 (114/152010) while in subpopulation NFE AF = 0.00134 (91/67962). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF8	NM_001271938.2 link	c.7567A>G	p.Thr2523Ala	missense_variant	Exon 42 of 42	ENST00000251268.11	NP_001258867.1	Q7Z7M0-1
MEGF8	NM_001410.3 link	c.7366A>G	p.Thr2456Ala	missense_variant	Exon 41 of 41		NP_001401.2	Q7Z7M0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11 link	c.7567A>G	p.Thr2523Ala	missense_variant	Exon 42 of 42	5	NM_001271938.2	ENSP00000251268.5		Q7Z7M0-1

Frequencies

GnomAD3 genomes

AF:

0.000751

AC:

114

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000734

AC:

181

AN:

246646

AF XY:

0.000775

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000668

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000967

AC:

1413

AN:

1460530

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

694

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000806

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.0000762

AC:

AN:

52466

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00117

AC:

1302

AN:

1111792

Other (OTH)

AF:

0.000762

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

196

294

392

490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.000750

AC:

114

AN:

152010

Hom.:

Cov.:

AF XY:

0.000740

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41464

American (AMR)

AF:

0.000851

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

67962

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.00118

Hom.:

Bravo

AF:

0.000850

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000684

AC:

EpiCase

AF:

0.00224

EpiControl

AF:

0.00166

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

MEGF8-related Carpenter syndrome

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.13

.;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;.;N

PhyloP100

0.53

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.022

Sift

Benign

0.69

T;T;T

Sift4G

Benign

0.99

T;D;T

Polyphen

0.0070

B;B;B

Vest4

0.078

MVP

0.082

MPC

0.55

ClinPred

0.0060

GERP RS

2.6

Varity_R

0.045

gMVP

0.47

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

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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