rs142221815

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001256545.2(MEGF10):​c.669T>A​(p.Asp223Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

MEGF10
NM_001256545.2 missense

Scores

2
17

Clinical Significance

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

Conservation

PhyloP100: 0.771
Variant links:
Genes affected
MEGF10 (HGNC:29634): (multiple EGF like domains 10) This gene encodes a member of the multiple epidermal growth factor-like domains protein family. The encoded protein plays a role in cell adhesion, motility and proliferation, and is a critical mediator of apoptotic cell phagocytosis as well as amyloid-beta peptide uptake in the brain. Expression of this gene may be associated with schizophrenia, and mutations in this gene are a cause of early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) as well as congenital myopathy with minicores. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.017832458).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MEGF10NM_001256545.2 linkuse as main transcriptc.669T>A p.Asp223Glu missense_variant 7/25 ENST00000503335.7 NP_001243474.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MEGF10ENST00000503335.7 linkuse as main transcriptc.669T>A p.Asp223Glu missense_variant 7/251 NM_001256545.2 ENSP00000423354 P1Q96KG7-1
MEGF10ENST00000274473.6 linkuse as main transcriptc.669T>A p.Asp223Glu missense_variant 8/261 ENSP00000274473 P1Q96KG7-1
MEGF10ENST00000418761.6 linkuse as main transcriptc.669T>A p.Asp223Glu missense_variant 8/151 ENSP00000416284 Q96KG7-2
MEGF10ENST00000508365.5 linkuse as main transcriptc.669T>A p.Asp223Glu missense_variant 7/141 ENSP00000423195 Q96KG7-2

Frequencies

GnomAD3 genomes
AF:
0.000355
AC:
54
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00125
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251424
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00129
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000349
AC:
51
AN:
1461782
Hom.:
0
Cov.:
31
AF XY:
0.0000344
AC XY:
25
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00137
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000355
AC:
54
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00125
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.0000904
Hom.:
0
Bravo
AF:
0.000412
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000107
AC:
13

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

MEGF10-related myopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 05, 2022This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 223 of the MEGF10 protein (p.Asp223Glu). This variant is present in population databases (rs142221815, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MEGF10-related conditions. ClinVar contains an entry for this variant (Variation ID: 350641). 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: "Benign"; Align-GVGD: "Class C35"). 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicAug 26, 2019- -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 09, 2021The c.669T>A (p.D223E) alteration is located in exon 8 (coding exon 6) of the MEGF10 gene. This alteration results from a T to A substitution at nucleotide position 669, causing the aspartic acid (D) at amino acid position 223 to be replaced by a glutamic acid (E). 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
0.19
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
15
DANN
Benign
0.64
DEOGEN2
Benign
0.011
T;.;.;T
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.53
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.78
.;.;T;T
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.018
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.47
N;N;N;N
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
0.44
N;N;N;N
REVEL
Benign
0.12
Sift
Benign
1.0
T;T;T;T
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.016
B;B;B;B
Vest4
0.36
MutPred
0.26
Gain of glycosylation at P227 (P = 0.1379);Gain of glycosylation at P227 (P = 0.1379);Gain of glycosylation at P227 (P = 0.1379);Gain of glycosylation at P227 (P = 0.1379);
MVP
0.13
MPC
0.21
ClinPred
0.0078
T
GERP RS
1.9
Varity_R
0.097
gMVP
0.18

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.

Other links and lift over

dbSNP: rs142221815; hg19: chr5-126734377; API