rs3025010

Variant names:

• chr6-43779840-T-C
• rs3025010
• NM_003376.6:c.963-892T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-43779840-T-C
• chr6-43779840-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003376.6(VEGFA):​c.963-892T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 403,106 control chromosomes in the GnomAD database, including 27,284 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 0.37 (10185 hom., cov: 32)
  • Exomes 𝑓: 0.37 (17099 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 62 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.399 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.963-892T>C		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.963-892T>C		intron	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.963-892T>C		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.963-892T>C		intron	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.963-892T>C		intron	N/A	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.962+922T>C		intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55940 AN: 151880 Hom.: 10170 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.343

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.365 AC: 91685 AN: 251104 Hom.: 17099 Cov.: 0 AF XY: 0.369 AC XY: 51744 AN XY: 140164

African (AFR) AF: 0.373 AC: 2789 AN: 7476

American (AMR) AF: 0.356 AC: 8317 AN: 23344

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 2190 AN: 7498

East Asian (EAS) AF: 0.291 AC: 2511 AN: 8618

South Asian (SAS) AF: 0.413 AC: 21065 AN: 50958

European-Finnish (FIN) AF: 0.400 AC: 4346 AN: 10860

Middle Eastern (MID) AF: 0.340 AC: 861 AN: 2534

European-Non Finnish (NFE) AF: 0.354 AC: 45312 AN: 127892

Other (OTH) AF: 0.360 AC: 4294 AN: 11924

GnomAD4 genome AF: 0.368 AC: 55999 AN: 152002 Hom.: 10185 Cov.: 32 AF XY: 0.372 AC XY: 27659 AN XY: 74278

African (AFR) AF: 0.380 AC: 15773 AN: 41464

American (AMR) AF: 0.346 AC: 5296 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1077 AN: 3460

East Asian (EAS) AF: 0.293 AC: 1510 AN: 5154

South Asian (SAS) AF: 0.414 AC: 1996 AN: 4824

European-Finnish (FIN) AF: 0.408 AC: 4317 AN: 10572

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.365 AC: 24794 AN: 67918

Other (OTH) AF: 0.348 AC: 735 AN: 2112

Alfa AF: 0.352 Hom.: 17562

Bravo AF: 0.360

Asia WGS AF: 0.397 AC: 1379 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.1
DANN	Benign	0.89
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs3025010; hg19: chr6-43747577; COSMIC: COSV57878529; COSMIC: COSV57878529;