chr6-43774682-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_003376.6(VEGFA):c.658+290G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 528,130 control chromosomes in the GnomAD database, including 32,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.37 ( 10703 hom., cov: 32)

Exomes 𝑓: 0.33 ( 21613 hom. )

Consequence

VEGFA
NM_003376.6 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.00500

Publications

5 publications found

Variant links:

Genes affected

VEGFA (HGNC:12680): (vascular endothelial growth factor A) This gene is a member of the PDGF/VEGF growth factor family. It encodes a heparin-binding protein, which exists as a disulfide-linked homodimer. This growth factor induces proliferation and migration of vascular endothelial cells, and is essential for both physiological and pathological angiogenesis. Disruption of this gene in mice resulted in abnormal embryonic blood vessel formation. This gene is upregulated in many known tumors and its expression is correlated with tumor stage and progression. Elevated levels of this protein are found in patients with POEMS syndrome, also known as Crow-Fukase syndrome. Allelic variants of this gene have been associated with microvascular complications of diabetes 1 (MVCD1) and atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been described. There is also evidence for alternative translation initiation from upstream non-AUG (CUG) codons resulting in additional isoforms. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is antiangiogenic. Expression of some isoforms derived from the AUG start codon is regulated by a small upstream open reading frame, which is located within an internal ribosome entry site. The levels of VEGF are increased during infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thus promoting inflammation by facilitating recruitment of inflammatory cells, and by increasing the level of angiopoietin II (Ang II), one of two products of the SARS-CoV-2 binding target, angiotensin-converting enzyme 2 (ACE2). In turn, Ang II facilitates the elevation of VEGF, thus forming a vicious cycle in the release of inflammatory cytokines. [provided by RefSeq, Jun 2020]

VEGFA Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

VEGFA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 6-43774682-G-C is Benign according to our data. Variant chr6-43774682-G-C is described in ClinVar as Benign. ClinVar VariationId is 1242677.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003376.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VEGFA	NM_003376.6	MANE Select	c.658+290G>C	intron	N/A	NP_003367.4
VEGFA	NM_001025366.3		c.658+290G>C	intron	N/A	NP_001020537.2	P15692-14
VEGFA	NM_001025367.3		c.658+290G>C	intron	N/A	NP_001020538.2	P15692-16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VEGFA	ENST00000672860.3	MANE Select	c.658+290G>C	intron	N/A	ENSP00000500082.3	P15692-13
VEGFA	ENST00000372055.9	TSL:1	c.658+290G>C	intron	N/A	ENSP00000361125.5	P15692-14
VEGFA	ENST00000425836.9	TSL:1	c.658+290G>C	intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes

AF:

0.367

AC:

55775

AN:

151918

Hom.:

10690

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.375

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.413

Gnomad SAS

AF:

0.276

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.394

GnomAD4 exome

AF:

0.332

AC:

124874

AN:

376094

Hom.:

21613

Cov.:

AF XY:

0.329

AC XY:

65077

AN XY:

197928

show subpopulations

African (AFR)

AF:

0.490

AC:

5336

AN:

10882

American (AMR)

AF:

0.371

AC:

6073

AN:

16362

Ashkenazi Jewish (ASJ)

AF:

0.431

AC:

5027

AN:

11664

East Asian (EAS)

AF:

0.439

AC:

11194

AN:

25508

South Asian (SAS)

AF:

0.278

AC:

11870

AN:

42650

European-Finnish (FIN)

AF:

0.237

AC:

5284

AN:

22288

Middle Eastern (MID)

AF:

0.413

AC:

669

AN:

1618

European-Non Finnish (NFE)

AF:

0.323

AC:

72094

AN:

223542

Other (OTH)

AF:

0.340

AC:

7327

AN:

21580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

3933

7867

11800

15734

19667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.367

AC:

55824

AN:

152036

Hom.:

10703

Cov.:

AF XY:

0.363

AC XY:

26949

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.485

AC:

20071

AN:

41424

American (AMR)

AF:

0.375

AC:

5733

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

1442

AN:

3472

East Asian (EAS)

AF:

0.414

AC:

2140

AN:

5170

South Asian (SAS)

AF:

0.276

AC:

1329

AN:

4820

European-Finnish (FIN)

AF:

0.232

AC:

2455

AN:

10596

Middle Eastern (MID)

AF:

0.415

AC:

122

AN:

294

European-Non Finnish (NFE)

AF:

0.317

AC:

21517

AN:

67950

Other (OTH)

AF:

0.395

AC:

835

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1801

3603

5404

7206

9007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

532

1064

1596

2128

2660

<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:

0.159

Hom.:

253

Bravo

AF:

0.399

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.0050

PromoterAI

0.026

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over