rs3025040

Variant names:

• chr6-43785314-C-A
• rs3025040
• NM_003376.6:c.*752C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-43785314-C-A
• chr6-43785314-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003376.6(VEGFA):​c.*752C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

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>A		3_prime_UTR	Exon 8 of 8	NP_003367.4
	VEGFA	NM_001025366.3		c.*752C>A		3_prime_UTR	Exon 8 of 8	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.*752C>A		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>A		3_prime_UTR	Exon 8 of 8	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000425836.9	TSL:1	c.*686C>A		3_prime_UTR	Exon 7 of 7	ENSP00000388465.4	A0A0A0MSH5
	VEGFA	ENST00000372067.8	TSL:1	c.*752C>A		3_prime_UTR	Exon 7 of 7	ENSP00000361137.4	P15692-11

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 57336 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 26708

African (AFR) AF: 0.00 AC: 0 AN: 2442

American (AMR) AF: 0.00 AC: 0 AN: 1594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3600

East Asian (EAS) AF: 0.00 AC: 0 AN: 8920

South Asian (SAS) AF: 0.00 AC: 0 AN: 504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 334

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 34740

Other (OTH) AF: 0.00 AC: 0 AN: 4736

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 945

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.97
DANN	Benign	0.76
PhyloP100		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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;