chr6-43770172-C-A

Position:

• chr6-43770172-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001318876.2(POLR1C):​c.945+240901C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 253,558 control chromosomes in the GnomAD database, including 18 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 0.0090 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0095 (9 hom.)
• Consequence: POLR1C NM_001318876.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.725

Genes affected

POLR1C (HGNC:):

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6			upstream_gene_variant		ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3			upstream_gene_variant			NM_003376.6	ENSP00000500082
VEGFA	ENST00000372067.8			upstream_gene_variant		1		ENSP00000361137
VEGFA	ENST00000425836.9			upstream_gene_variant		1		ENSP00000388465
VEGFA	ENST00000476772.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00902 AC: 1367 AN: 151512 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00396

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00529

GnomAD4 exome AF: 0.00951 AC: 969 AN: 101936 Hom.: 9 Cov.: 0 AF XY: 0.00919 AC XY: 449 AN XY: 48864

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.00605

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.000592

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00900 AC: 1365 AN: 151622 Hom.: 9 Cov.: 31 AF XY: 0.00874 AC XY: 648 AN XY: 74108

Gnomad4 AFR AF: 0.00268

Gnomad4 AMR AF: 0.00452

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00396

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00523

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00789

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs36208384; hg19: chr6-43737909;