6-43773714-G-T

Position:

• chr6-43773714-G-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.607-627G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 157,354 control chromosomes in the GnomAD database, including 8 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 0.0087 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (0 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296

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=-0.8).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00874 (1330/152136) while in subpopulation SAS AF= 0.0342 (165/4820). AF 95% confidence interval is 0.03. There are 8 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFA	NM_003376.6	c.607-627G>T		intron_variant		ENST00000672860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFA	ENST00000672860.3	c.607-627G>T		intron_variant			NM_003376.6

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1329 AN: 152018 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00958 AC: 50 AN: 5218 Hom.: 0 Cov.: 0 AF XY: 0.0114 AC XY: 32 AN XY: 2796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00431

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00957

Gnomad4 OTH exome AF: 0.0179

GnomAD4 genome AF: 0.00874 AC: 1330 AN: 152136 Hom.: 8 Cov.: 32 AF XY: 0.00834 AC XY: 620 AN XY: 74370

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000970

Gnomad4 SAS AF: 0.0342

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0111 Hom.: 0

Bravo AF: 0.00848

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.77

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: rs3025042; hg19: chr6-43741451;