rs947345

chr1-3507824-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001409.4(MEGF6):c.1760C>T(p.Pro587Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0505 in 1,612,602 control chromosomes in the GnomAD database, including 2,351 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.060 (368 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1983 hom.)
• Consequence: MEGF6 NM_001409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60

Genes affected

MEGF6 (HGNC:3232): (multiple EGF like domains 6) Predicted to enable calcium ion binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003544271).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF6	NM_001409.4	c.1760C>T	p.Pro587Leu	missense_variant	14/37	ENST00000356575.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF6	ENST00000356575.9	c.1760C>T	p.Pro587Leu	missense_variant	14/37	1	NM_001409.4	P1
MEGF6	ENST00000294599.8	c.1445C>T	p.Pro482Leu	missense_variant	11/30	1
MEGF6	ENST00000697102.1	c.1445C>T	p.Pro482Leu	missense_variant	11/34
MEGF6	ENST00000485002.6	c.1781C>T	p.Pro594Leu	missense_variant, NMD_transcript_variant	14/37	5

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9133 AN: 152114 Hom.: 366 Cov.: 33

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0681

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0410

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0483

Gnomad OTH AF: 0.0507

GnomAD3 exomes AF: 0.0473 AC: 11750 AN: 248558 Hom.: 336 AF XY: 0.0459 AC XY: 6203 AN XY: 135116

Gnomad AFR exome AF: 0.0971

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0647

Gnomad EAS exome AF: 0.0508

Gnomad SAS exome AF: 0.0239

Gnomad FIN exome AF: 0.0437

Gnomad NFE exome AF: 0.0495

Gnomad OTH exome AF: 0.0513

GnomAD4 exome AF: 0.0495 AC: 72265 AN: 1460368 Hom.: 1983 Cov.: 32 AF XY: 0.0487 AC XY: 35347 AN XY: 726464

Gnomad4 AFR exome AF: 0.0981

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.0653

Gnomad4 EAS exome AF: 0.0577

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.0436

Gnomad4 NFE exome AF: 0.0503

Gnomad4 OTH exome AF: 0.0499

GnomAD4 genome AF: 0.0601 AC: 9156 AN: 152234 Hom.: 368 Cov.: 33 AF XY: 0.0588 AC XY: 4375 AN XY: 74436

Gnomad4 AFR AF: 0.0979

Gnomad4 AMR AF: 0.0436

Gnomad4 ASJ AF: 0.0681

Gnomad4 EAS AF: 0.0499

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.0410

Gnomad4 NFE AF: 0.0482

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0523 Hom.: 278

Bravo AF: 0.0644

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0496 AC: 191

ESP6500AA AF: 0.0925 AC: 375

ESP6500EA AF: 0.0505 AC: 421

ExAC AF: 0.0471 AC: 5700

Asia WGS AF: 0.0350 AC: 122 AN: 3478

EpiCase AF: 0.0538

EpiControl AF: 0.0556

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;D
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.000039	P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-9.6	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.21
MPC		0.53
ClinPred		0.052	T
GERP RS		4.2
Varity_R		0.35
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs947345; hg19: chr1-3424388; COSMIC: COSV53888452;