NM_001271938.2:c.2450A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001271938.2(MEGF8):c.2450A>G(p.His817Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000573 in 1,612,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. H817Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.86

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009564936).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000493 (75/152252) while in subpopulation SAS AF = 0.00228 (11/4832). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 35 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271938.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF8	NM_001271938.2	MANE Select	c.2450A>G	p.His817Arg	missense	Exon 14 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.2249A>G	p.His750Arg	missense	Exon 13 of 41	NP_001401.2	Q7Z7M0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEGF8	ENST00000251268.11	TSL:5 MANE Select	c.2450A>G	p.His817Arg	missense	Exon 14 of 42	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8	TSL:1	c.2249A>G	p.His750Arg	missense	Exon 13 of 41	ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5	TSL:5	c.-4636A>G		5_prime_UTR	Exon 14 of 41	ENSP00000367313.4	F5GZG7

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000555

AC:

138

AN:

248504

AF XY:

0.000632

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000611

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000582

AC:

849

AN:

1459812

Hom.:

Cov.:

AF XY:

0.000633

AC XY:

460

AN XY:

726248

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000671

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51578

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000586

AC:

651

AN:

1111834

Other (OTH)

AF:

0.000431

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000493

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41538

American (AMR)

AF:

0.000849

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00228

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000574

AC:

AN:

68000

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000421

Hom.:

Bravo

AF:

0.000431

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000577

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

MEGF8-related Carpenter syndrome (3)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.10

Eigen

Benign

-0.074

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

M_CAP

Benign

0.024

MetaRNN

Benign

0.0096

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

3.9

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.6

REVEL

Benign

0.069

Sift

Benign

0.17

Sift4G

Benign

0.15

Polyphen

0.56

Vest4

0.32

MVP

0.11

MPC

0.76

ClinPred

0.021

GERP RS

3.5

Varity_R

0.12

gMVP

0.49

Mutation Taster

=83/17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over