rs3812054

Variant names:

• chr5-127396735-G-A
• rs3812054
• NM_001256545.2:c.616G>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.616G>A​(p.Val206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,958 control chromosomes in the GnomAD database, including 13,248 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (958 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12290 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.601
• Publications: 23 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015771091).
• BP6: Variant 5-127396735-G-A is Benign according to our data. Variant chr5-127396735-G-A is described in ClinVar as Benign. ClinVar VariationId is 262079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	NM_001256545.2	MANE Select	c.616G>A	p.Val206Ile	missense	Exon 6 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.616G>A	p.Val206Ile	missense	Exon 7 of 26	NP_115822.1	Q96KG7-1
	MEGF10	NM_001308119.2		c.616G>A	p.Val206Ile	missense	Exon 7 of 15	NP_001295048.1	Q96KG7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.616G>A	p.Val206Ile	missense	Exon 6 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.616G>A	p.Val206Ile	missense	Exon 7 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000418761.6	TSL:1	c.616G>A	p.Val206Ile	missense	Exon 7 of 15	ENSP00000416284.2	Q96KG7-2

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16401 AN: 152160 Hom.: 956 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.110 AC: 27684 AN: 250708 AF XY: 0.112

Gnomad AFR exome AF: 0.0679

Gnomad AMR exome AF: 0.0610

Gnomad ASJ exome AF: 0.0968

Gnomad EAS exome AF: 0.0506

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.127 AC: 185530 AN: 1461680 Hom.: 12290 Cov.: 33 AF XY: 0.126 AC XY: 91700 AN XY: 727142

African (AFR) AF: 0.0668 AC: 2235 AN: 33480

American (AMR) AF: 0.0632 AC: 2828 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0900 AC: 2351 AN: 26134

East Asian (EAS) AF: 0.0719 AC: 2853 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8861 AN: 86258

European-Finnish (FIN) AF: 0.152 AC: 8122 AN: 53266

Middle Eastern (MID) AF: 0.0685 AC: 395 AN: 5768

European-Non Finnish (NFE) AF: 0.136 AC: 151085 AN: 1111958

Other (OTH) AF: 0.113 AC: 6800 AN: 60392

GnomAD4 genome AF: 0.108 AC: 16408 AN: 152278 Hom.: 958 Cov.: 32 AF XY: 0.107 AC XY: 7979 AN XY: 74462

African (AFR) AF: 0.0707 AC: 2940 AN: 41560

American (AMR) AF: 0.0829 AC: 1269 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3468

East Asian (EAS) AF: 0.0585 AC: 303 AN: 5180

South Asian (SAS) AF: 0.117 AC: 563 AN: 4822

European-Finnish (FIN) AF: 0.144 AC: 1527 AN: 10612

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9174 AN: 68012

Other (OTH) AF: 0.106 AC: 224 AN: 2116

Alfa AF: 0.120 Hom.: 4315

Bravo AF: 0.0987

TwinsUK AF: 0.139 AC: 515

ALSPAC AF: 0.134 AC: 516

ESP6500AA AF: 0.0654 AC: 288

ESP6500EA AF: 0.130 AC: 1120

ExAC AF: 0.113 AC: 13766

Asia WGS AF: 0.0770 AC: 269 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.122

ClinVar

ClinVar submissions

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	0.062
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.2
DANN	Benign	0.89
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.86	L
PhyloP100		0.60
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.013
Sift	Benign	0.40	T
Sift4G	Benign	0.21	T
Polyphen		0.0030	B
Vest4		0.042
MPC		0.18
ClinPred		0.00017	T
GERP RS		0.79
Varity_R		0.0097
gMVP		0.052
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: rs3812054; hg19: chr5-126732427; COSMIC: COSV57248712;