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

Variant summary

Our verdict is Benign. The variant received -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.

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

Publications

14 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.0473

AC:

11750

AN:

248558

AF XY:

0.0459

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 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

African (AFR)

AF:

0.0981

AC:

3282

AN:

33466

American (AMR)

AF:

0.0362

AC:

1616

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0653

AC:

1706

AN:

26128

East Asian (EAS)

AF:

0.0577

AC:

2291

AN:

39690

South Asian (SAS)

AF:

0.0228

AC:

1970

AN:

86236

European-Finnish (FIN)

AF:

0.0436

AC:

2275

AN:

52226

Middle Eastern (MID)

AF:

0.0404

AC:

233

AN:

5766

European-Non Finnish (NFE)

AF:

0.0503

AC:

55878

AN:

1111804

Other (OTH)

AF:

0.0499

AC:

3014

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3739

7477

11216

14954

18693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2168

4336

6504

8672

10840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0601

AC:

9156

AN:

152234

Hom.:

368

Cov.:

AF XY:

0.0588

AC XY:

4375

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0979

AC:

4064

AN:

41528

American (AMR)

AF:

0.0436

AC:

667

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0681

AC:

236

AN:

3468

East Asian (EAS)

AF:

0.0499

AC:

258

AN:

5172

South Asian (SAS)

AF:

0.0191

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0410

AC:

435

AN:

10606

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0482

AC:

3281

AN:

68022

Other (OTH)

AF:

0.0502

AC:

106

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

445

890

1335

1780

2225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0531

Hom.:

797

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

(source)

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

PhyloP100

5.6

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

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over