6-43781426-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003376.6(VEGFA):c.1035-530T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 236,326 control chromosomes in the GnomAD database, including 56,800 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 0.70 (37417 hom., cov: 36)
  • Exomes 𝑓: 0.67 (19383 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.604

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]

POLR1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFA	NM_003376.6	c.1035-530T>C		intron_variant		ENST00000672860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFA	ENST00000672860.3	c.1035-530T>C		intron_variant			NM_003376.6

Frequencies

GnomAD3 genomes AF: 0.699 AC: 106264 AN: 152102 Hom.: 37367 Cov.: 36

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.673

GnomAD4 exome AF: 0.671 AC: 56394 AN: 84106 Hom.: 19383 Cov.: 0 AF XY: 0.676 AC XY: 29757 AN XY: 44042

Gnomad4 AFR exome AF: 0.757

Gnomad4 AMR exome AF: 0.689

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.855

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.634

Gnomad4 NFE exome AF: 0.647

Gnomad4 OTH exome AF: 0.653

GnomAD4 genome AF: 0.699 AC: 106376 AN: 152220 Hom.: 37417 Cov.: 36 AF XY: 0.700 AC XY: 52094 AN XY: 74418

Gnomad4 AFR AF: 0.763

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.625

Gnomad4 EAS AF: 0.856

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.654

Gnomad4 NFE AF: 0.665

Gnomad4 OTH AF: 0.675

Alfa AF: 0.683 Hom.: 7408

Bravo AF: 0.701

Asia WGS AF: 0.773 AC: 2689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	10
Dann	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs3025021; hg19: chr6-43749163;