6-43771240-C-T

Variant names:

• chr6-43771240-C-T
• rs25648
• ENST00000523873:c.-7C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BA1

The NM_001171623.2(VEGFA):​c.-7C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,606,202 control chromosomes in the GnomAD database, including 22,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (1671 hom., cov: 33)
  • Exomes 𝑓: 0.17 (20492 hom.)
• Consequence: VEGFA NM_001171623.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-43771240-C-T is Benign according to our data. Variant chr6-43771240-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.534C>T	p.Ser178Ser	synonymous_variant	Exon 1 of 8	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.534C>T	p.Ser178Ser	synonymous_variant	Exon 1 of 8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21830 AN: 151958 Hom.: 1669 Cov.: 33

Gnomad AFR AF: 0.0852

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.155 AC: 36307 AN: 234132 Hom.: 2924 AF XY: 0.155 AC XY: 20104 AN XY: 129378

Gnomad AFR exome AF: 0.0829

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.0788

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.167 AC: 242512 AN: 1454136 Hom.: 20492 Cov.: 36 AF XY: 0.167 AC XY: 120513 AN XY: 723588

Gnomad4 AFR exome AF: 0.0856

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.144 AC: 21848 AN: 152066 Hom.: 1671 Cov.: 33 AF XY: 0.146 AC XY: 10831 AN XY: 74330

Gnomad4 AFR AF: 0.0852

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.0946

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.129

Alfa AF: 0.159 Hom.: 2453

Bravo AF: 0.135

Asia WGS AF: 0.175 AC: 607 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.97

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: rs25648; hg19: chr6-43738977; COSMIC: COSV57878509; COSMIC: COSV57878509;