chr5-127449091-T-G

Position:

• chr5-127449091-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001256545.2(MEGF10):​c.2857-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,986 control chromosomes in the GnomAD database, including 8 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: MEGF10 NM_001256545.2 splice_region, intron
• Scores: Splicing: ADA: 0.04685
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.09

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-127449091-T-G is Benign according to our data. Variant chr5-127449091-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383117.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00116 (177/152318) while in subpopulation AMR AF= 0.00333 (51/15300). AF 95% confidence interval is 0.0026. There are 1 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.2857-8T>G		splice_region_variant, intron_variant		ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.2857-8T>G		splice_region_variant, intron_variant		1	NM_001256545.2	ENSP00000423354.2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00126 AC: 317 AN: 250738 Hom.: 2 AF XY: 0.00133 AC XY: 180 AN XY: 135666

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.00125 AC: 1828 AN: 1461668 Hom.: 7 Cov.: 30 AF XY: 0.00129 AC XY: 939 AN XY: 727126

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00119 AC XY: 89 AN XY: 74496

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00124

EpiCase AF: 0.00142

EpiControl AF: 0.00208

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MEGF10-related myopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.047
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201148765; hg19: chr5-126784783;