Genetic Variant NM_001256545.2:c.3003C>A (chr5-127454588-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001256545.2(MEGF10):c.3003C>A(p.Ser1001Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1001S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MEGF10
NM_001256545.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.440

Publications

0 publications found

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]

MEGF10 Gene-Disease associations (from GenCC):

MEGF10-related myopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

MEGF10 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08191523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2 link	c.3003C>A	p.Ser1001Arg	missense_variant	Exon 23 of 25	ENST00000503335.7	NP_001243474.1	Q96KG7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF10	ENST00000503335.7 link	c.3003C>A	p.Ser1001Arg	missense_variant	Exon 23 of 25	1	NM_001256545.2	ENSP00000423354.2	Q96KG7-1
MEGF10	ENST00000274473.6 link	c.3003C>A	p.Ser1001Arg	missense_variant	Exon 24 of 26	1		ENSP00000274473.6	Q96KG7-1
MEGF10	ENST00000510828.5 link	n.502C>A		non_coding_transcript_exon_variant	Exon 5 of 6	5
MEGF10	ENST00000515622.1 link	n.204C>A		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455568

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723896

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33084

American (AMR)

AF:

0.00

AC:

AN:

43804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.00

AC:

AN:

84546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109616

Other (OTH)

AF:

0.00

AC:

AN:

60092

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

9.0

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.73

.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.082

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

PhyloP100

-0.44

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.17

Sift

Benign

0.92

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0

B;B

Vest4

0.31

MutPred

0.40

Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);

MVP

0.15

MPC

0.25

ClinPred

0.24

GERP RS

1.4

Varity_R

0.033

gMVP

0.44

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over