rs865577

Positions:

• chr6-43774682-G-C
• chr6-43774682-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003376.6(VEGFA):​c.658+290G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 528,130 control chromosomes in the GnomAD database, including 32,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10703 hom., cov: 32)
  • Exomes 𝑓: 0.33 (21613 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00500

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 6-43774682-G-C is Benign according to our data. Variant chr6-43774682-G-C is described in ClinVar as [Benign]. Clinvar id is 1242677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.658+290G>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.658+290G>C		intron_variant			NM_003376.6	ENSP00000500082

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55775 AN: 151918 Hom.: 10690 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.394

GnomAD4 exome AF: 0.332 AC: 124874 AN: 376094 Hom.: 21613 Cov.: 2 AF XY: 0.329 AC XY: 65077 AN XY: 197928

Gnomad4 AFR exome AF: 0.490

Gnomad4 AMR exome AF: 0.371

Gnomad4 ASJ exome AF: 0.431

Gnomad4 EAS exome AF: 0.439

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.340

GnomAD4 genome AF: 0.367 AC: 55824 AN: 152036 Hom.: 10703 Cov.: 32 AF XY: 0.363 AC XY: 26949 AN XY: 74320

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.414

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.395

Alfa AF: 0.159 Hom.: 253

Bravo AF: 0.399

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.85

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: rs865577; hg19: chr6-43742419;