19-42351670-C-T

Position:

chr19-42351670-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF8	NM_001271938.2 linkuse as main transcript	c.3010C>T	p.Arg1004Trp	missense_variant	18/42	ENST00000251268.11	NP_001258867.1
MEGF8	NM_001410.3 linkuse as main transcript	c.2809C>T	p.Arg937Trp	missense_variant	17/41		NP_001401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF8	ENST00000251268.11 linkuse as main transcript	c.3010C>T	p.Arg1004Trp	missense_variant	18/42	5	NM_001271938.2	ENSP00000251268	A2	Q7Z7M0-1
MEGF8	ENST00000334370.8 linkuse as main transcript	c.2809C>T	p.Arg937Trp	missense_variant	17/41	1		ENSP00000334219	P2	Q7Z7M0-2
MEGF8	ENST00000378073.5 linkuse as main transcript	c.-4076C>T		5_prime_UTR_variant	18/41	5		ENSP00000367313

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

GnomAD3 exomes

AF:

0.000559

AC:

118

AN:

211216

Hom.:

AF XY:

0.000526

AC XY:

AN XY:

114074

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 SAS 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

Gnomad4 AFR exome

AF:

0.000274

Gnomad4 AMR exome

AF:

0.0000978

Gnomad4 ASJ exome

AF:

0.00121

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000364

Gnomad4 FIN exome

AF:

0.0000971

Gnomad4 NFE exome

AF:

0.00150

Gnomad4 OTH exome

AF:

0.000740

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152282

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00110

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

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 18, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2022	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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

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

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

MutationTaster

Benign

0.86

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over