rs6595769

Variant names:

• chr5-127398673-C-T
• rs6595769
• NM_001256545.2:c.660-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_032446.3(MEGF10):​c.660-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,692 control chromosomes in the GnomAD database, including 21,498 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3348 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18150 hom.)
• Consequence: MEGF10 NM_032446.3 splice_region, intron
• Scores: Splicing: ADA: 0.003024
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.97
• Publications: 9 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 5-127398673-C-T is Benign according to our data. Variant chr5-127398673-C-T is described in ClinVar as Benign. ClinVar VariationId is 262080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032446.3. 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.660-3C>T		splice_region intron	N/A	NP_001243474.1
	MEGF10	NM_032446.3		c.660-3C>T		splice_region intron	N/A	NP_115822.1
	MEGF10	NM_001308119.2		c.660-3C>T		splice_region intron	N/A	NP_001295048.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.660-3C>T		splice_region intron	N/A	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.660-3C>T		splice_region intron	N/A	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.660-3C>T		splice_region intron	N/A	ENSP00000416284.2

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29378 AN: 152056 Hom.: 3333 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.153 AC: 38556 AN: 251306 AF XY: 0.153

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.0873

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.0985

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.154 AC: 224672 AN: 1461520 Hom.: 18150 Cov.: 32 AF XY: 0.153 AC XY: 111256 AN XY: 727076

African (AFR) AF: 0.317 AC: 10611 AN: 33470

American (AMR) AF: 0.0894 AC: 4000 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3592 AN: 26130

East Asian (EAS) AF: 0.110 AC: 4353 AN: 39696

South Asian (SAS) AF: 0.169 AC: 14530 AN: 86226

European-Finnish (FIN) AF: 0.170 AC: 9058 AN: 53404

Middle Eastern (MID) AF: 0.103 AC: 589 AN: 5722

European-Non Finnish (NFE) AF: 0.152 AC: 168821 AN: 1111772

Other (OTH) AF: 0.151 AC: 9118 AN: 60378

GnomAD4 genome AF: 0.193 AC: 29422 AN: 152172 Hom.: 3348 Cov.: 32 AF XY: 0.191 AC XY: 14233 AN XY: 74400

African (AFR) AF: 0.317 AC: 13155 AN: 41492

American (AMR) AF: 0.121 AC: 1849 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3468

East Asian (EAS) AF: 0.106 AC: 548 AN: 5186

South Asian (SAS) AF: 0.194 AC: 937 AN: 4818

European-Finnish (FIN) AF: 0.163 AC: 1732 AN: 10604

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10218 AN: 67998

Other (OTH) AF: 0.168 AC: 354 AN: 2110

Alfa AF: 0.172 Hom.: 1398

Bravo AF: 0.194

Asia WGS AF: 0.139 AC: 488 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	MEGF10-related myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.020		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: rs6595769; hg19: chr5-126734365; COSMIC: COSV57245990;