rs56302402

Positions:

• chr6-43774220-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003376.6(VEGFA):​c.607-121A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,040,106 control chromosomes in the GnomAD database, including 71 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 0.0069 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (58 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78

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=-0.76).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00677 (6008/887842) while in subpopulation MID AF= 0.054 (173/3204). AF 95% confidence interval is 0.0474. There are 58 homozygotes in gnomad4_exome. There are 3322 alleles in male gnomad4_exome subpopulation. Median coverage is 12. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1052 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.607-121A>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.607-121A>T		intron_variant			NM_003376.6	ENSP00000500082

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1051 AN: 152146 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.00677 AC: 6008 AN: 887842 Hom.: 58 Cov.: 12 AF XY: 0.00721 AC XY: 3322 AN XY: 460660

Gnomad4 AFR exome AF: 0.00722

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.0361

Gnomad4 EAS exome AF: 0.0000286

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.000904

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00691 AC: 1052 AN: 152264 Hom.: 13 Cov.: 32 AF XY: 0.00647 AC XY: 482 AN XY: 74448

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00587

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00641 Hom.: 0

Bravo AF: 0.00826

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.5
DANN	Benign	0.84

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: rs56302402; hg19: chr6-43741957;