6-43778432-C-T

Position:

• chr6-43778432-C-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.856-28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,609,198 control chromosomes in the GnomAD database, including 71,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4923 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66618 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=-0.56).
• BP6: Variant 6-43778432-C-T is Benign according to our data. Variant chr6-43778432-C-T is described in ClinVar as [Benign]. Clinvar id is 1259260.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.856-28C>T		intron_variant		ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.856-28C>T		intron_variant			NM_003376.6	ENSP00000500082

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35240 AN: 152062 Hom.: 4921 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.290 AC: 72129 AN: 248984 Hom.: 11079 AF XY: 0.290 AC XY: 39052 AN XY: 134606

Gnomad AFR exome AF: 0.0581

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.400

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.297 AC: 433047 AN: 1457018 Hom.: 66618 Cov.: 31 AF XY: 0.297 AC XY: 214996 AN XY: 725010

Gnomad4 AFR exome AF: 0.0519

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.415

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.232 AC: 35250 AN: 152180 Hom.: 4923 Cov.: 32 AF XY: 0.230 AC XY: 17123 AN XY: 74392

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.289

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.267

Alfa AF: 0.224 Hom.: 1009

Bravo AF: 0.234

Asia WGS AF: 0.270 AC: 937 AN: 3478

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	-0.56
CADD	Benign	14
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: rs3025000; hg19: chr6-43746169; COSMIC: COSV57879845; COSMIC: COSV57879845;