chr6-43778432-C-T

Variant names:

• chr6-43778432-C-T
• rs3025000
• NM_003376.6:c.856-28C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 67 publications found

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]

VEGFA Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003376.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.856-28C>T		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.856-28C>T		intron	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.856-28C>T		intron	N/A	NP_001020538.2	P15692-16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.856-28C>T		intron	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.856-28C>T		intron	N/A	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.856-28C>T		intron	N/A	ENSP00000388465.4	A0A0A0MSH5

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

GnomAD2 exomes AF: 0.290 AC: 72129 AN: 248984 AF XY: 0.290

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 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

African (AFR) AF: 0.0519 AC: 1733 AN: 33380

American (AMR) AF: 0.325 AC: 14463 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9561 AN: 26096

East Asian (EAS) AF: 0.415 AC: 16436 AN: 39614

South Asian (SAS) AF: 0.247 AC: 21222 AN: 86072

European-Finnish (FIN) AF: 0.234 AC: 12443 AN: 53248

Middle Eastern (MID) AF: 0.278 AC: 1578 AN: 5672

European-Non Finnish (NFE) AF: 0.306 AC: 338640 AN: 1108214

Other (OTH) AF: 0.282 AC: 16971 AN: 60242

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

African (AFR) AF: 0.0658 AC: 2734 AN: 41566

American (AMR) AF: 0.289 AC: 4414 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1263 AN: 3472

East Asian (EAS) AF: 0.398 AC: 2054 AN: 5160

South Asian (SAS) AF: 0.249 AC: 1201 AN: 4824

European-Finnish (FIN) AF: 0.228 AC: 2410 AN: 10590

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20361 AN: 67958

Other (OTH) AF: 0.267 AC: 565 AN: 2116

Alfa AF: 0.273 Hom.: 12159

Bravo AF: 0.234

Asia WGS AF: 0.270 AC: 937 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		0.0050
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3025000; hg19: chr6-43746169; COSMIC: COSV57879845; COSMIC: COSV57879845;