5-127454588-C-T

Variant names:

• chr5-127454588-C-T
• rs35159176
• NM_001256545.2:c.3003C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001256545.2(MEGF10):​c.3003C>T​(p.Ser1001Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,607,542 control chromosomes in the GnomAD database, including 10 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 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (10 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.440
• 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, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 5-127454588-C-T is Benign according to our data. Variant chr5-127454588-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262073.
• BP7: Synonymous conserved (PhyloP=-0.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00201 (306/152128) while in subpopulation AMR AF = 0.00628 (96/15284). AF 95% confidence interval is 0.00526. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.3003C>T	p.Ser1001Ser	synonymous	Exon 23 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.3003C>T	p.Ser1001Ser	synonymous	Exon 24 of 26	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.3003C>T	p.Ser1001Ser	synonymous	Exon 23 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.3003C>T	p.Ser1001Ser	synonymous	Exon 24 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000510828.5	TSL:5	n.502C>T		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00178 AC: 437 AN: 245676 AF XY: 0.00185

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.00282

Gnomad ASJ exome AF: 0.00111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00270 AC: 3932 AN: 1455414 Hom.: 10 Cov.: 30 AF XY: 0.00264 AC XY: 1913 AN XY: 723834

African (AFR) AF: 0.000846 AC: 28 AN: 33082

American (AMR) AF: 0.00281 AC: 123 AN: 43796

Ashkenazi Jewish (ASJ) AF: 0.000925 AC: 24 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 84546

European-Finnish (FIN) AF: 0.000507 AC: 27 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00324 AC: 3598 AN: 1109478

Other (OTH) AF: 0.00220 AC: 132 AN: 60088

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74368

African (AFR) AF: 0.000651 AC: 27 AN: 41484

American (AMR) AF: 0.00628 AC: 96 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00249 AC: 169 AN: 68006

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00244

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.3
DANN	Benign	0.68
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35159176; hg19: chr5-126790280;