rs41282644

Positions:

• chr6-43785985-G-A
• chr6-43785985-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_003376.6(VEGFA):​c.*1423G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0421 in 180,106 control chromosomes in the GnomAD database, including 248 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 0.042 (201 hom., cov: 32)
  • Exomes 𝑓: 0.045 (47 hom.)
• Consequence: VEGFA NM_003376.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.*1423G>A		3_prime_UTR_variant	8/8	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.*1423G>A		3_prime_UTR_variant	8/8		NM_003376.6	ENSP00000500082

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6300 AN: 151372 Hom.: 201 Cov.: 32

Gnomad AFR AF: 0.00983

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0421

Gnomad FIN AF: 0.0984

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0551

Gnomad OTH AF: 0.0452

GnomAD4 exome AF: 0.0452 AC: 1293 AN: 28620 Hom.: 47 Cov.: 0 AF XY: 0.0451 AC XY: 598 AN XY: 13262

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0381

Gnomad4 ASJ exome AF: 0.0650

Gnomad4 EAS exome AF: 0.00152

Gnomad4 SAS exome AF: 0.0381

Gnomad4 FIN exome AF: 0.0928

Gnomad4 NFE exome AF: 0.0568

Gnomad4 OTH exome AF: 0.0491

GnomAD4 genome AF: 0.0415 AC: 6294 AN: 151486 Hom.: 201 Cov.: 32 AF XY: 0.0432 AC XY: 3199 AN XY: 73988

Gnomad4 AFR AF: 0.00980

Gnomad4 AMR AF: 0.0345

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0415

Gnomad4 FIN AF: 0.0984

Gnomad4 NFE AF: 0.0551

Gnomad4 OTH AF: 0.0448

Alfa AF: 0.0519 Hom.: 190

Bravo AF: 0.0349

Asia WGS AF: 0.0180 AC: 65 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs41282644; hg19: chr6-43753722;