6-43778673-C-T

Variant names:

• chr6-43778673-C-T
• rs3025047
• ENST00000476772.5:n.1592C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000476772.5(VEGFA):​n.1592C>T 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 0.00894 in 1,068,890 control chromosomes in the GnomAD database, including 74 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 0.0072 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (67 hom.)
• Consequence: VEGFA ENST00000476772.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.779
• Publications: 8 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS2: High AC in GnomAd4 at 1097 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.932+137C>T		intron_variant	Intron 4 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.932+137C>T		intron_variant	Intron 4 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152158 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00923 AC: 8462 AN: 916614 Hom.: 67 Cov.: 13 AF XY: 0.00889 AC XY: 4197 AN XY: 471870

African (AFR) AF: 0.00172 AC: 38 AN: 22056

American (AMR) AF: 0.00330 AC: 117 AN: 35464

Ashkenazi Jewish (ASJ) AF: 0.00136 AC: 30 AN: 22140

East Asian (EAS) AF: 0.000118 AC: 4 AN: 33822

South Asian (SAS) AF: 0.00239 AC: 167 AN: 69890

European-Finnish (FIN) AF: 0.0205 AC: 975 AN: 47500

Middle Eastern (MID) AF: 0.00445 AC: 21 AN: 4718

European-Non Finnish (NFE) AF: 0.0106 AC: 6792 AN: 638798

Other (OTH) AF: 0.00753 AC: 318 AN: 42226

GnomAD4 genome AF: 0.00720 AC: 1097 AN: 152276 Hom.: 7 Cov.: 33 AF XY: 0.00714 AC XY: 532 AN XY: 74460

African (AFR) AF: 0.00221 AC: 92 AN: 41554

American (AMR) AF: 0.00248 AC: 38 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.0187 AC: 198 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 741 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00970 Hom.: 14

Bravo AF: 0.00626

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.9
DANN	Benign	0.83
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism

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: rs3025047; hg19: chr6-43746410;