rs1345662

Variant names:

• chr5-127299975-G-C
• rs1345662
• NM_001256545.2:c.-19+8919G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001256545.2(MEGF10):​c.-19+8919G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 151,934 control chromosomes in the GnomAD database, including 22,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.53 (22334 hom., cov: 31)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: MEGF10 NM_001256545.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.886
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-127299975-G-C is Benign according to our data. Variant chr5-127299975-G-C is described in ClinVar as [Benign]. Clinvar id is 1295222.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.-19+8919G>C		intron_variant	Intron 1 of 24	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.-19+8919G>C		intron_variant	Intron 1 of 24	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.-69-21G>C		intron_variant	Intron 1 of 25	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.-69-21G>C		intron_variant	Intron 1 of 14	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.-19+8919G>C		intron_variant	Intron 1 of 13	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80939 AN: 151812 Hom.: 22317 Cov.: 31

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.550

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.533 AC: 80988 AN: 151930 Hom.: 22334 Cov.: 31 AF XY: 0.524 AC XY: 38877 AN XY: 74240

African (AFR) AF: 0.439 AC: 18178 AN: 41402

American (AMR) AF: 0.508 AC: 7758 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1900 AN: 3468

East Asian (EAS) AF: 0.276 AC: 1429 AN: 5170

South Asian (SAS) AF: 0.415 AC: 1999 AN: 4822

European-Finnish (FIN) AF: 0.516 AC: 5438 AN: 10532

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42218 AN: 67952

Other (OTH) AF: 0.555 AC: 1171 AN: 2110

Alfa AF: 0.366 Hom.: 774

Bravo AF: 0.527

Asia WGS AF: 0.397 AC: 1383 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1345662; hg19: chr5-126635667; COSMIC: COSV57246575;