rs141383715

Variant names:

Your query was ambiguous. Multiple possible variants found:

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: 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 -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

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.3010C>T	p.Arg1004Trp	missense	Exon 18 of 42	NP_001258867.1	Q7Z7M0-1
	MEGF8	NM_001410.3		c.2809C>T	p.Arg937Trp	missense	Exon 17 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.3010C>T	p.Arg1004Trp	missense	Exon 18 of 42	ENSP00000251268.5	Q7Z7M0-1
MEGF8	ENST00000334370.8	TSL:1	c.2809C>T	p.Arg937Trp	missense	Exon 17 of 41	ENSP00000334219.4	Q7Z7M0-2
MEGF8	ENST00000378073.5	TSL:5	c.-4076C>T		5_prime_UTR_premature_start_codon_gain	Exon 18 of 41	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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

MEGF8-related Carpenter syndrome (3)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.062

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.21

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0070

Polyphen

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over