ENST00000476772.5:n.430C>G

Variant names:

• chr6-43770613-C-G
• rs2010963
• ENST00000476772.5:n.430C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000476772.5(VEGFA):​n.430C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,449,354 control chromosomes in the GnomAD database, including 339,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35366 hom., cov: 33)
  • Exomes 𝑓: 0.68 (304109 hom.)
• Consequence: VEGFA ENST00000476772.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.03
• Publications: 979 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]

ENSG00000272114 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-43770613-C-G is Benign according to our data. Variant chr6-43770613-C-G is described in ClinVar as [Benign]. Clinvar id is 12223.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.-94C>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.-94C>G		5_prime_UTR_variant	Exon 1 of 8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103572 AN: 151946 Hom.: 35315 Cov.: 33

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.686

Gnomad OTH AF: 0.651

GnomAD4 exome AF: 0.684 AC: 886758 AN: 1297288 Hom.: 304109 Cov.: 57 AF XY: 0.684 AC XY: 436658 AN XY: 638118

African (AFR) AF: 0.682 AC: 17853 AN: 26166

American (AMR) AF: 0.662 AC: 13922 AN: 21040

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 12178 AN: 20870

East Asian (EAS) AF: 0.578 AC: 17211 AN: 29752

South Asian (SAS) AF: 0.729 AC: 49096 AN: 67388

European-Finnish (FIN) AF: 0.764 AC: 24470 AN: 32024

Middle Eastern (MID) AF: 0.614 AC: 2896 AN: 4718

European-Non Finnish (NFE) AF: 0.684 AC: 712359 AN: 1041272

Other (OTH) AF: 0.680 AC: 36773 AN: 54058

GnomAD4 genome AF: 0.682 AC: 103677 AN: 152066 Hom.: 35366 Cov.: 33 AF XY: 0.686 AC XY: 51010 AN XY: 74322

African (AFR) AF: 0.675 AC: 28021 AN: 41496

American (AMR) AF: 0.654 AC: 10000 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2044 AN: 3470

East Asian (EAS) AF: 0.596 AC: 3052 AN: 5124

South Asian (SAS) AF: 0.726 AC: 3507 AN: 4828

European-Finnish (FIN) AF: 0.770 AC: 8148 AN: 10586

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.686 AC: 46619 AN: 67964

Other (OTH) AF: 0.649 AC: 1371 AN: 2112

Alfa AF: 0.632 Hom.: 1917

Bravo AF: 0.666

Asia WGS AF: 0.699 AC: 2435 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27648002, 25992764, 23957473, 25328912, 22993299, 15338501, 11978667, 24205329, 23007030, 16142870, 19653005, 23353010, 10930302, 15963467) -

Microvascular complications of diabetes, susceptibility to, 1 Other:1

May 01, 2002

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		1.0
PromoterAI		-0.075	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2010963; hg19: chr6-43738350;