chr4-176684029-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005429.5(VEGFC):​c.1157G>A​(p.Arg386Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

VEGFC
NM_005429.5 missense

Scores

3
13

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.33
Variant links:
Genes affected
VEGFC (HGNC:12682): (vascular endothelial growth factor C) The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. The encoded protein promotes angiogenesis and endothelial cell growth, and can also affect the permeability of blood vessels. The proprotein is further cleaved into a fully processed form that can bind and activate VEGFR-2 and VEGFR-3 receptors. [provided by RefSeq, Apr 2014]
HAFML (HGNC:56694): (HuR (ELAVL1) associated fibroblast migratory lncRNA)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.25716165).
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VEGFCNM_005429.5 linkuse as main transcriptc.1157G>A p.Arg386Gln missense_variant 7/7 ENST00000618562.2
HAFMLNR_183975.1 linkuse as main transcriptn.182+14320C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VEGFCENST00000618562.2 linkuse as main transcriptc.1157G>A p.Arg386Gln missense_variant 7/71 NM_005429.5 P1
HAFMLENST00000509194.1 linkuse as main transcriptn.89+14320C>T intron_variant, non_coding_transcript_variant 3
HAFMLENST00000504017.5 linkuse as main transcriptn.140+4279C>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000803
AC:
2
AN:
249032
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135158
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461618
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727146
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

VEGFC-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 23, 2024The VEGFC c.1157G>A variant is predicted to result in the amino acid substitution p.Arg386Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T
Eigen
Benign
0.13
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.0058
T
MetaRNN
Benign
0.26
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
0.56
D
PrimateAI
Benign
0.38
T
Sift4G
Benign
0.33
T
Polyphen
0.84
P
Vest4
0.22
MVP
0.23
ClinPred
0.87
D
GERP RS
4.7
Varity_R
0.099
gMVP
0.41

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: rs368084817; hg19: chr4-177605183; COSMIC: COSV54601636; API