dbSNP rs947345: MEGF6:p.Pro587Leu (chr1-3507824-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.060 ( 368 hom., cov: 33)

Exomes 𝑓: 0.049 ( 1983 hom. )

Consequence

MEGF6
NM_001409.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.60

Variant links:

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]

MEGF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MEGF6	NM_001409.4 link	c.1760C>T	p.Pro587Leu	missense_variant	Exon 14 of 37	ENST00000356575.9	NP_001400.3	O75095-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF6	ENST00000356575.9 link	c.1760C>T	p.Pro587Leu	missense_variant	Exon 14 of 37	1	NM_001409.4	ENSP00000348982.4	O75095-1
MEGF6	ENST00000294599.8 link	c.1445C>T	p.Pro482Leu	missense_variant	Exon 11 of 30	1		ENSP00000294599.4	O75095-2
MEGF6	ENST00000697102.1 link	c.1445C>T	p.Pro482Leu	missense_variant	Exon 11 of 34			ENSP00000513108.1	A0A8V8TL19
MEGF6	ENST00000485002.6 link	n.1781C>T		non_coding_transcript_exon_variant	Exon 14 of 37	5		ENSP00000419033.2	H7C557

Frequencies

GnomAD3 genomes

AF:

0.0600

AC:

9133

AN:

152114

Hom.:

366

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0487

AC XY:

35347

AN XY:

726464

show subpopulations

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.:

AF XY:

0.0588

AC XY:

4375

AN XY:

74436

show subpopulations

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

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

.;T

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

T;D

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Uncertain

0.50

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over