rs1885657

Positions:

• chr6-43772357-T-C
• chr6-43772357-T-G

Variant summary

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

The NM_003376.6(VEGFA):​c.606+1045T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,158 control chromosomes in the GnomAD database, including 5,732 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 0.26 (5732 hom., cov: 33)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.342

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.606+1045T>C		intron_variant		ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.606+1045T>C		intron_variant			NM_003376.6	ENSP00000500082

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39383 AN: 152038 Hom.: 5716 Cov.: 33

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.259 AC: 39442 AN: 152158 Hom.: 5732 Cov.: 33 AF XY: 0.262 AC XY: 19528 AN XY: 74410

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.256

Alfa AF: 0.154 Hom.: 446

Bravo AF: 0.265

Asia WGS AF: 0.300 AC: 1045 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1885657; hg19: chr6-43740094;