Genetic Variant VEGFA:c.-663C>T (chr6-43770044-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003376.6(VEGFA):c.-663C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 294,866 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0069 ( 18 hom., cov: 33)

Exomes 𝑓: 0.0063 ( 10 hom. )

Consequence

VEGFA
NM_003376.6 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.43

Publications

13 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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6 link	c.-663C>T		upstream_gene_variant		ENST00000672860.3	NP_003367.4	P15692-13

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
VEGFA	ENST00000672860.3 link	c.-663C>T	upstream_gene_variant		NM_003376.6	ENSP00000500082.3	P15692-13A0A5F9ZH41
VEGFA	ENST00000425836.9 link	c.-663C>T	upstream_gene_variant	1		ENSP00000388465.4	A0A0A0MSH5
VEGFA	ENST00000372067.8 link	c.-663C>T	upstream_gene_variant	1		ENSP00000361137.4	P15692-11H3BLW8
VEGFA	ENST00000476772.5 link	n.-140C>T	upstream_gene_variant	1

Frequencies

GnomAD3 genomes

AF:

0.00688

AC:

1047

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0592

Gnomad SAS

AF:

0.0434

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.00535

Gnomad OTH

AF:

0.00860

GnomAD4 exome

AF:

0.00634

AC:

904

AN:

142650

Hom.:

AF XY:

0.00602

AC XY:

423

AN XY:

70212

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

4752

American (AMR)

AF:

0.00129

AC:

AN:

3870

Ashkenazi Jewish (ASJ)

AF:

0.00215

AC:

AN:

6512

East Asian (EAS)

AF:

0.0227

AC:

385

AN:

16984

South Asian (SAS)

AF:

0.0261

AC:

AN:

1190

European-Finnish (FIN)

AF:

0.000756

AC:

AN:

9258

Middle Eastern (MID)

AF:

0.0184

AC:

AN:

762

European-Non Finnish (NFE)

AF:

0.00423

AC:

378

AN:

89408

Other (OTH)

AF:

0.00635

AC:

AN:

9914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00686

AC:

1044

AN:

152216

Hom.:

Cov.:

AF XY:

0.00712

AC XY:

530

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41546

American (AMR)

AF:

0.00405

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.0594

AC:

307

AN:

5172

South Asian (SAS)

AF:

0.0428

AC:

206

AN:

4814

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00535

AC:

364

AN:

67974

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000958

Hom.:

Bravo

AF:

0.00618

Asia WGS

AF:

0.0330

AC:

115

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.5

(source)

DANN

Benign

0.95

PhyloP100

-1.4

PromoterAI

-0.031

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over