6-43785314-C-T

Variant names:

• chr6-43785314-C-T
• rs3025040
• NM_003376.6:c.*752C>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.*752C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 209,370 control chromosomes in the GnomAD database, including 2,376 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 0.15 (1734 hom., cov: 31)
  • Exomes 𝑓: 0.15 (642 hom.)
• Consequence: VEGFA NM_003376.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• Publications: 42 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.179 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.*752C>T		3_prime_UTR	Exon 8 of 8	NP_003367.4
	VEGFA	NM_001025366.3		c.*752C>T		3_prime_UTR	Exon 8 of 8	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.*752C>T		3_prime_UTR	Exon 8 of 8	NP_001020538.2	P15692-16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.*752C>T		3_prime_UTR	Exon 8 of 8	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000425836.9	TSL:1	c.*686C>T		3_prime_UTR	Exon 7 of 7	ENSP00000388465.4	A0A0A0MSH5
	VEGFA	ENST00000372067.8	TSL:1	c.*752C>T		3_prime_UTR	Exon 7 of 7	ENSP00000361137.4	P15692-11

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22108 AN: 152010 Hom.: 1732 Cov.: 31

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.0974

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.148 AC: 8448 AN: 57242 Hom.: 642 Cov.: 0 AF XY: 0.148 AC XY: 3952 AN XY: 26672

African (AFR) AF: 0.137 AC: 334 AN: 2440

American (AMR) AF: 0.211 AC: 335 AN: 1590

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 451 AN: 3596

East Asian (EAS) AF: 0.193 AC: 1715 AN: 8894

South Asian (SAS) AF: 0.0956 AC: 48 AN: 502

European-Finnish (FIN) AF: 0.152 AC: 71 AN: 466

Middle Eastern (MID) AF: 0.138 AC: 46 AN: 334

European-Non Finnish (NFE) AF: 0.138 AC: 4779 AN: 34692

Other (OTH) AF: 0.141 AC: 669 AN: 4728

GnomAD4 genome AF: 0.145 AC: 22127 AN: 152128 Hom.: 1734 Cov.: 31 AF XY: 0.146 AC XY: 10825 AN XY: 74372

African (AFR) AF: 0.137 AC: 5686 AN: 41482

American (AMR) AF: 0.184 AC: 2817 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3472

East Asian (EAS) AF: 0.178 AC: 918 AN: 5166

South Asian (SAS) AF: 0.0983 AC: 474 AN: 4822

European-Finnish (FIN) AF: 0.155 AC: 1646 AN: 10588

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.143 AC: 9707 AN: 67992

Other (OTH) AF: 0.145 AC: 306 AN: 2112

Alfa AF: 0.137 Hom.: 945

Bravo AF: 0.152

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.79
PhyloP100		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3025040; hg19: chr6-43753051; COSMIC: COSV57877549; COSMIC: COSV57877549;