9-120605605-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080497.3(MEGF9):ā€‹c.1394T>Cā€‹(p.Leu465Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,592,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000028 ( 0 hom. )

Consequence

MEGF9
NM_001080497.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22
Variant links:
Genes affected
MEGF9 (HGNC:3234): (multiple EGF like domains 9) Predicted to be involved in several processes, including animal organ morphogenesis; cell migration; and substrate adhesion-dependent cell spreading. Predicted to be integral component of membrane. Predicted to be active in basement membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07255277).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MEGF9NM_001080497.3 linkc.1394T>C p.Leu465Ser missense_variant 6/6 ENST00000373930.4 NP_001073966.2 Q9H1U4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MEGF9ENST00000373930.4 linkc.1394T>C p.Leu465Ser missense_variant 6/62 NM_001080497.3 ENSP00000363040.3 Q9H1U4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152244
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000477
AC:
1
AN:
209538
Hom.:
0
AF XY:
0.00000888
AC XY:
1
AN XY:
112648
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000658
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000278
AC:
4
AN:
1439844
Hom.:
0
Cov.:
31
AF XY:
0.00000140
AC XY:
1
AN XY:
714110
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000511
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000182
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152362
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74516
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 31, 2024The c.1394T>C (p.L465S) alteration is located in exon 6 (coding exon 6) of the MEGF9 gene. This alteration results from a T to C substitution at nucleotide position 1394, causing the leucine (L) at amino acid position 465 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
0.18
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0068
T
Eigen
Benign
-0.14
Eigen_PC
Benign
0.073
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0030
T
MetaRNN
Benign
0.073
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.20
N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.29
N
REVEL
Benign
0.090
Sift
Benign
0.12
T
Sift4G
Benign
0.32
T
Vest4
0.072
MVP
0.043
ClinPred
0.21
T
GERP RS
5.6
Varity_R
0.049
gMVP
0.78

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

LitVar

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

Other links and lift over

dbSNP: rs1305861614; hg19: chr9-123367883; API