NM_001256545.2:c.3215G>A

Variant names:

• chr5-127455590-G-A
• rs17164935
• NM_001256545.2:c.3215G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):​c.3215G>A​(p.Arg1072Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,490 control chromosomes in the GnomAD database, including 20,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1072N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1560 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18690 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.40
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012667179).
• BP6: Variant 5-127455590-G-A is Benign according to our data. Variant chr5-127455590-G-A is described in ClinVar as Benign. ClinVar VariationId is 262075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	NM_001256545.2	MANE Select	c.3215G>A	p.Arg1072Lys	missense	Exon 24 of 25	NP_001243474.1
	MEGF10	NM_032446.3		c.3215G>A	p.Arg1072Lys	missense	Exon 25 of 26	NP_115822.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.3215G>A	p.Arg1072Lys	missense	Exon 24 of 25	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.3215G>A	p.Arg1072Lys	missense	Exon 25 of 26	ENSP00000274473.6
	MEGF10	ENST00000515622.1	TSL:2	n.416G>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21417 AN: 152038 Hom.: 1556 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.138 AC: 34687 AN: 250580 AF XY: 0.140

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0776

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.0957

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.158 AC: 230230 AN: 1461334 Hom.: 18690 Cov.: 32 AF XY: 0.157 AC XY: 113846 AN XY: 726972

African (AFR) AF: 0.106 AC: 3544 AN: 33456

American (AMR) AF: 0.0801 AC: 3580 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3035 AN: 26124

East Asian (EAS) AF: 0.109 AC: 4318 AN: 39658

South Asian (SAS) AF: 0.121 AC: 10428 AN: 86236

European-Finnish (FIN) AF: 0.183 AC: 9782 AN: 53400

Middle Eastern (MID) AF: 0.114 AC: 657 AN: 5766

European-Non Finnish (NFE) AF: 0.167 AC: 185991 AN: 1111612

Other (OTH) AF: 0.147 AC: 8895 AN: 60376

GnomAD4 genome AF: 0.141 AC: 21448 AN: 152156 Hom.: 1560 Cov.: 32 AF XY: 0.138 AC XY: 10282 AN XY: 74378

African (AFR) AF: 0.111 AC: 4620 AN: 41504

American (AMR) AF: 0.106 AC: 1626 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 443 AN: 3472

East Asian (EAS) AF: 0.103 AC: 536 AN: 5180

South Asian (SAS) AF: 0.134 AC: 644 AN: 4818

European-Finnish (FIN) AF: 0.174 AC: 1838 AN: 10562

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11314 AN: 68008

Other (OTH) AF: 0.135 AC: 285 AN: 2114

Alfa AF: 0.153 Hom.: 8064

Bravo AF: 0.132

TwinsUK AF: 0.171 AC: 633

ALSPAC AF: 0.166 AC: 641

ESP6500AA AF: 0.106 AC: 465

ESP6500EA AF: 0.163 AC: 1404

ExAC AF: 0.141 AC: 17180

Asia WGS AF: 0.111 AC: 388 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.149

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	MEGF10-related myopathy (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.76
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PhyloP100		3.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.22
ClinPred		0.0026	T
GERP RS		3.0
Varity_R		0.034
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17164935; hg19: chr5-126791282; COSMIC: COSV57245824; COSMIC: COSV57245824;