chr6-43776884-C-T

Variant names:

• chr6-43776884-C-T
• rs735286
• NM_003376.6:c.659-585C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003376.6(VEGFA):​c.659-585C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 175,790 control chromosomes in the GnomAD database, including 5,853 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 0.23 (4964 hom., cov: 33)
  • Exomes 𝑓: 0.26 (889 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 9 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.659-585C>T		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.659-585C>T		intron	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.659-585C>T		intron	N/A	NP_001020538.2	P15692-16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.659-585C>T		intron	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.659-585C>T		intron	N/A	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.659-585C>T		intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35296 AN: 152138 Hom.: 4960 Cov.: 33

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.263

GnomAD4 exome AF: 0.257 AC: 6052 AN: 23534 Hom.: 889 Cov.: 0 AF XY: 0.258 AC XY: 3178 AN XY: 12322

African (AFR) AF: 0.0430 AC: 44 AN: 1024

American (AMR) AF: 0.292 AC: 934 AN: 3198

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 143 AN: 446

East Asian (EAS) AF: 0.373 AC: 720 AN: 1930

South Asian (SAS) AF: 0.213 AC: 571 AN: 2680

European-Finnish (FIN) AF: 0.188 AC: 90 AN: 478

Middle Eastern (MID) AF: 0.289 AC: 22 AN: 76

European-Non Finnish (NFE) AF: 0.259 AC: 3284 AN: 12690

Other (OTH) AF: 0.241 AC: 244 AN: 1012

GnomAD4 genome AF: 0.232 AC: 35304 AN: 152256 Hom.: 4964 Cov.: 33 AF XY: 0.231 AC XY: 17177 AN XY: 74450

African (AFR) AF: 0.0639 AC: 2655 AN: 41574

American (AMR) AF: 0.292 AC: 4461 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1261 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2095 AN: 5182

South Asian (SAS) AF: 0.251 AC: 1213 AN: 4824

European-Finnish (FIN) AF: 0.228 AC: 2422 AN: 10604

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20400 AN: 67996

Other (OTH) AF: 0.266 AC: 562 AN: 2112

Alfa AF: 0.291 Hom.: 4229

Bravo AF: 0.234

Asia WGS AF: 0.273 AC: 949 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.6
DANN	Benign	0.83
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs735286; hg19: chr6-43744621;