5-127340614-C-A

Variant names:

• chr5-127340614-C-A
• NM_001256545.2:c.303C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001256545.2(MEGF10):​c.303C>A​(p.Ser101Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.303C>A	p.Ser101Arg	missense_variant	Exon 4 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.303C>A	p.Ser101Arg	missense_variant	Exon 4 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.303C>A	p.Ser101Arg	missense_variant	Exon 5 of 26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.303C>A	p.Ser101Arg	missense_variant	Exon 5 of 15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.303C>A	p.Ser101Arg	missense_variant	Exon 4 of 14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460192 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.85	.;.;T;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.78
MutPred		0.55		Loss of glycosylation at S101 (P = 0.0538);Loss of glycosylation at S101 (P = 0.0538);Loss of glycosylation at S101 (P = 0.0538);Loss of glycosylation at S101 (P = 0.0538);
MVP		0.42
MPC		0.49
ClinPred		0.99	D
GERP RS		0.94
Varity_R		0.53
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-126676306;