rs148814585

Variant names:

• chr5-127434831-G-A
• rs148814585
• NM_001256545.2:c.1975+10G>A

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.1975+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,610,420 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (3 hom.)
• Consequence: MEGF10 NM_001256545.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.46
• Publications: 0 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 (BayesDel_noAF=-0.92).
• BP6: Variant 5-127434831-G-A is Benign according to our data. Variant chr5-127434831-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 511785.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000749 (114/152268) while in subpopulation NFE AF = 0.000823 (56/68026). AF 95% confidence interval is 0.000651. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1975+10G>A		intron	N/A	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.1975+10G>A		intron	N/A	NP_115822.1	Q96KG7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.1975+10G>A		intron	N/A	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.1975+10G>A		intron	N/A	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000506709.1	TSL:3	n.216+10G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000683 AC: 168 AN: 246140 AF XY: 0.000705

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00839

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000254

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000555 AC: 810 AN: 1458152 Hom.: 3 Cov.: 30 AF XY: 0.000515 AC XY: 374 AN XY: 725514

African (AFR) AF: 0.000209 AC: 7 AN: 33452

American (AMR) AF: 0.000135 AC: 6 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 261 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.0000983 AC: 5 AN: 50844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000434 AC: 482 AN: 1111406

Other (OTH) AF: 0.000812 AC: 49 AN: 60334

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74448

African (AFR) AF: 0.000289 AC: 12 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000725

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.046
DANN	Benign	0.50
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs148814585; hg19: chr5-126770523; COSMIC: COSV57244611;