rs78847357

Variant names:

• chr5-127410517-G-A
• rs78847357
• NM_001256545.2:c.1046G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-127410517-G-A
• chr5-127410517-G-C
• chr5-127410517-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001256545.2(MEGF10):​c.1046G>A​(p.Arg349His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,842 control chromosomes in the GnomAD database, including 12 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R349C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (5 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.325
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007239789).
• BP6: Variant 5-127410517-G-A is Benign according to our data. Variant chr5-127410517-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262059.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00532 (810/152348) while in subpopulation AFR AF = 0.0173 (718/41580). AF 95% confidence interval is 0.0162. There are 7 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1046G>A	p.Arg349His	missense	Exon 9 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.1046G>A	p.Arg349His	missense	Exon 10 of 26	NP_115822.1	Q96KG7-1
	MEGF10	NM_001308119.2		c.1046G>A	p.Arg349His	missense	Exon 10 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.1046G>A	p.Arg349His	missense	Exon 9 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.1046G>A	p.Arg349His	missense	Exon 10 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000418761.6	TSL:1	c.1046G>A	p.Arg349His	missense	Exon 10 of 15	ENSP00000416284.2	Q96KG7-2

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 808 AN: 152230 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00138 AC: 347 AN: 250664 AF XY: 0.000974

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000589 AC: 861 AN: 1461494 Hom.: 5 Cov.: 31 AF XY: 0.000509 AC XY: 370 AN XY: 727030

African (AFR) AF: 0.0191 AC: 638 AN: 33478

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5762

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111994

Other (OTH) AF: 0.00137 AC: 83 AN: 60394

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152348 Hom.: 7 Cov.: 33 AF XY: 0.00518 AC XY: 386 AN XY: 74504

African (AFR) AF: 0.0173 AC: 718 AN: 41580

American (AMR) AF: 0.00451 AC: 69 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00157 Hom.: 4

Bravo AF: 0.00591

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00166 AC: 202

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	MEGF10-related myopathy (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.10
DANN	Benign	0.94
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N
PhyloP100		-0.33
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.052
Sift	Benign	0.43	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.094
MVP		0.26
MPC		0.27
ClinPred		0.00048	T
GERP RS		-4.7
Varity_R		0.020
gMVP		0.21
Mutation Taster		=99/1	polymorphism

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: rs78847357; hg19: chr5-126746209;