19-42333743-C-T

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.326C>T(p.Pro109Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,844 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 (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

MEGF8
NM_001271938.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.34

Publications

1 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04519835).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000636 (93/1461626) while in subpopulation SAS AF = 0.000777 (67/86256). AF 95% confidence interval is 0.000627. There are 0 homozygotes in GnomAdExome4. There are 65 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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.326C>T	p.Pro109Leu	missense_variant	Exon 2 of 42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3 link	c.326C>T	p.Pro109Leu	missense_variant	Exon 2 of 41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MEGF8	ENST00000251268.11 link	c.326C>T	p.Pro109Leu	missense_variant	Exon 2 of 42	5	NM_001271938.2	ENSP00000251268.5
MEGF8	ENST00000334370.8 link	c.326C>T	p.Pro109Leu	missense_variant	Exon 2 of 41	1		ENSP00000334219.4
MEGF8	ENST00000378073.5 link	c.-6760C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 41	5		ENSP00000367313.4
MEGF8	ENST00000378073.5 link	c.-6760C>T		5_prime_UTR_variant	Exon 2 of 41	5		ENSP00000367313.4

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000117

AC:

AN:

248734

AF XY:

0.000170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000777

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111842

Other (OTH)

AF:

0.0000331

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.0000279

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 02, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MEGF8-related Carpenter syndrome

Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 109 of the MEGF8 protein (p.Pro109Leu). This variant is present in population databases (rs768036287, gnomAD 0.09%). 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: 435856). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.326C>T (p.P109L) alteration is located in exon 2 (coding exon 2) of the MEGF8 gene. This alteration results from a C to T substitution at nucleotide position 326, causing the proline (P) at amino acid position 109 to be replaced by a leucine (L). 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

0.072

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.045

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L

PhyloP100

2.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.11

Sift

Benign

0.32

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;.

Vest4

0.42

MutPred

0.51

Loss of glycosylation at P109 (P = 0.0093);Loss of glycosylation at P109 (P = 0.0093);

MVP

0.043

MPC

0.39

ClinPred

0.063

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.052

gMVP

0.15

Mutation Taster

=79/21

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