rs56302402

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003376.6(VEGFA):c.607-121A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,040,106 control chromosomes in the GnomAD database, including 71 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 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 58 hom. )

Consequence

VEGFA
NM_003376.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.78

Publications

1 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00677 (6008/887842) while in subpopulation MID AF = 0.054 (173/3204). AF 95% confidence interval is 0.0474. There are 58 homozygotes in GnomAdExome4. There are 3322 alleles in the male GnomAdExome4 subpopulation. Median coverage is 12. This position passed quality control check.

BS2

High AC in GnomAd4 at 1052 AD gene.

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.607-121A>T	intron	N/A	NP_003367.4
VEGFA	NM_001025366.3		c.607-121A>T	intron	N/A	NP_001020537.2	P15692-14
VEGFA	NM_001025367.3		c.607-121A>T	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.607-121A>T	intron	N/A	ENSP00000500082.3	P15692-13
VEGFA	ENST00000372055.9	TSL:1	c.607-121A>T	intron	N/A	ENSP00000361125.5	P15692-14
VEGFA	ENST00000425836.9	TSL:1	c.607-121A>T	intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes

AF:

0.00691

AC:

1051

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00596

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00744

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.00587

Gnomad OTH

AF:

0.0172

GnomAD4 exome

AF:

0.00677

AC:

6008

AN:

887842

Hom.:

Cov.:

AF XY:

0.00721

AC XY:

3322

AN XY:

460660

show subpopulations

African (AFR)

AF:

0.00722

AC:

160

AN:

22166

American (AMR)

AF:

0.00926

AC:

347

AN:

37458

Ashkenazi Jewish (ASJ)

AF:

0.0361

AC:

796

AN:

22068

East Asian (EAS)

AF:

0.0000286

AC:

AN:

34920

South Asian (SAS)

AF:

0.0116

AC:

827

AN:

71360

European-Finnish (FIN)

AF:

0.000904

AC:

AN:

46450

Middle Eastern (MID)

AF:

0.0540

AC:

173

AN:

3204

European-Non Finnish (NFE)

AF:

0.00531

AC:

3236

AN:

608868

Other (OTH)

AF:

0.0103

AC:

426

AN:

41348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

333

665

998

1330

1663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.00691

AC:

1052

AN:

152264

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

482

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00597

AC:

248

AN:

41542

American (AMR)

AF:

0.0120

AC:

184

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00766

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00587

AC:

399

AN:

68008

Other (OTH)

AF:

0.0170

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

107

161

214

268

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:

0.00641

Hom.:

Bravo

AF:

0.00826

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.5

(source)

DANN

Benign

0.84

PhyloP100

-1.8

PromoterAI

-0.0071

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

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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