ENST00000480614.1:n.4199G>A

Variant names:

• chr6-43777370-G-A
• rs3024997
• ENST00000480614.1:n.4199G>A

Variant summary

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

The ENST00000480614.1(VEGFA):​n.4199G>A 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 0.318 in 1,383,676 control chromosomes in the GnomAD database, including 71,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (7692 hom., cov: 32)
  • Exomes 𝑓: 0.32 (63634 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.58
• Publications: 40 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-43777370-G-A is Benign according to our data. Variant chr6-43777370-G-A is described in ClinVar as Benign. ClinVar VariationId is 1233590.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.659-99G>A		intron_variant	Intron 2 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.659-99G>A		intron_variant	Intron 2 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48185 AN: 152014 Hom.: 7683 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.318 AC: 391233 AN: 1231544 Hom.: 63634 Cov.: 17 AF XY: 0.317 AC XY: 196645 AN XY: 621126

African (AFR) AF: 0.321 AC: 9318 AN: 29016

American (AMR) AF: 0.361 AC: 14816 AN: 41076

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 10078 AN: 24512

East Asian (EAS) AF: 0.435 AC: 16443 AN: 37766

South Asian (SAS) AF: 0.271 AC: 21485 AN: 79148

European-Finnish (FIN) AF: 0.235 AC: 10682 AN: 45418

Middle Eastern (MID) AF: 0.398 AC: 1525 AN: 3832

European-Non Finnish (NFE) AF: 0.316 AC: 290119 AN: 918124

Other (OTH) AF: 0.318 AC: 16767 AN: 52652

GnomAD4 genome AF: 0.317 AC: 48206 AN: 152132 Hom.: 7692 Cov.: 32 AF XY: 0.313 AC XY: 23246 AN XY: 74350

African (AFR) AF: 0.323 AC: 13404 AN: 41466

American (AMR) AF: 0.345 AC: 5286 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1406 AN: 3472

East Asian (EAS) AF: 0.417 AC: 2155 AN: 5168

South Asian (SAS) AF: 0.271 AC: 1308 AN: 4818

European-Finnish (FIN) AF: 0.231 AC: 2443 AN: 10594

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.312 AC: 21188 AN: 67994

Other (OTH) AF: 0.348 AC: 734 AN: 2112

Alfa AF: 0.320 Hom.: 3261

Bravo AF: 0.333

Asia WGS AF: 0.303 AC: 1054 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign: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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.026
DANN	Benign	0.56
PhyloP100		-2.6
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: rs3024997; hg19: chr6-43745107; COSMIC: COSV57879996; COSMIC: COSV57879996;