chr4-176687827-C-T

Position:

chr4-176687827-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005429.5(VEGFC):c.805G>A(p.Gly269Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000335 in 1,609,718 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

VEGFC
NM_005429.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.19

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]

VEGFC links:

HAFML (HGNC:56694): (HuR (ELAVL1) associated fibroblast migratory lncRNA)

HAFML links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09688923).

BP6

Variant 4-176687827-C-T is Benign according to our data. Variant chr4-176687827-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1686366.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFC	NM_005429.5 linkuse as main transcript	c.805G>A	p.Gly269Arg	missense_variant	5/7	ENST00000618562.2
HAFML	NR_183975.1 linkuse as main transcript	n.183-18076C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
VEGFC	ENST00000618562.2 linkuse as main transcript	c.805G>A	p.Gly269Arg	missense_variant	5/7	1	NM_005429.5	P1
HAFML	ENST00000509194.1 linkuse as main transcript	n.90-18076C>T		intron_variant, non_coding_transcript_variant		3
HAFML	ENST00000504017.5 linkuse as main transcript	n.140+8077C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000372

AC:

AN:

247444

Hom.:

AF XY:

0.000432

AC XY:

AN XY:

134268

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.000412

Gnomad ASJ exome

AF:

0.000301

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000265

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000524

Gnomad OTH exome

AF:

0.000668

GnomAD4 exome

AF:

0.000336

AC:

490

AN:

1457408

Hom.:

Cov.:

AF XY:

0.000365

AC XY:

265

AN XY:

725204

show subpopulations

Gnomad4 AFR exome

AF:

0.000270

Gnomad4 AMR exome

AF:

0.000361

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000326

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000355

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000328

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000438

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000729

AC:

ExAC

AF:

0.000447

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.805G>A (p.G269R) alteration is located in exon 5 (coding exon 5) of the VEGFC gene. This alteration results from a G to A substitution at nucleotide position 805, causing the glycine (G) at amino acid position 269 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

0.0066

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.60

M_CAP

Benign

0.0019

MetaRNN

Benign

0.097

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.99

PrimateAI

Benign

0.38

Sift4G

Benign

0.46

Polyphen

0.36

Vest4

0.43

MutPred

0.17

Gain of glycosylation at T273 (P = 0.0522);

MVP

0.34

ClinPred

0.038

GERP RS

5.3

Varity_R

0.096

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over