GeneBe

rs772343967

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001409.4(MEGF6):​c.4240G>A​(p.Gly1414Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000879 in 1,604,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

MEGF6
NM_001409.4 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEGF6NM_001409.4 linkc.4240G>A p.Gly1414Ser missense_variant Exon 33 of 37 ENST00000356575.9 NP_001400.3 O75095-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEGF6ENST00000356575.9 linkc.4240G>A p.Gly1414Ser missense_variant Exon 33 of 37 1 NM_001409.4 ENSP00000348982.4 O75095-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152126
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000615
AC:
14
AN:
227820
AF XY:
0.0000479
show subpopulations
Gnomad AFR exome
AF:
0.0000776
Gnomad AMR exome
AF:
0.0000309
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000509
Gnomad NFE exome
AF:
0.0000982
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000930
AC:
135
AN:
1452286
Hom.:
0
Cov.:
32
AF XY:
0.0000845
AC XY:
61
AN XY:
721974
show subpopulations
African (AFR)
AF:
0.000120
AC:
4
AN:
33278
American (AMR)
AF:
0.0000465
AC:
2
AN:
43056
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25924
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39260
South Asian (SAS)
AF:
0.0000705
AC:
6
AN:
85094
European-Finnish (FIN)
AF:
0.0000389
AC:
2
AN:
51394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5746
European-Non Finnish (NFE)
AF:
0.000101
AC:
112
AN:
1108534
Other (OTH)
AF:
0.000150
AC:
9
AN:
60000
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
8
16
24
32
40
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.0000394
AC:
6
AN:
152126
Hom.:
0
Cov.:
34
AF XY:
0.0000404
AC XY:
3
AN XY:
74312
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41426
American (AMR)
AF:
0.0000655
AC:
1
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000823
Hom.:
0
Bravo
AF:
0.0000869
ExAC
AF:
0.0000418
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 15, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.4240G>A (p.G1414S) alteration is located in exon 33 (coding exon 33) of the MEGF6 gene. This alteration results from a G to A substitution at nucleotide position 4240, causing the glycine (G) at amino acid position 1414 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.00055
T
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.82
T
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.6
H
PhyloP100
3.9
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-5.1
D
REVEL
Uncertain
0.60
Sift
Uncertain
0.016
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.62
MVP
0.59
MPC
0.26
ClinPred
0.96
D
GERP RS
4.0
Varity_R
0.76
gMVP
0.70
Mutation Taster
=62/38
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

Publications

LitVar

Below is the list of publications found by LitVar for variant 1:3494014 C>T . It may be empty.

Other links and lift over

dbSNP: rs772343967; hg19: chr1-3410578; API