6-43770770-C-T

Variant names:

• chr6-43770770-C-T
• rs764480708
• NM_003376.6:c.64C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003376.6(VEGFA):​c.64C>T​(p.Arg22Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,482,002 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: VEGFA NM_003376.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 0.0430
• Publications: 1 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

ENSG00000272114 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009267122).
• BS2: High AC in GnomAd4 at 103 AD gene.

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.64C>T	p.Arg22Trp	missense	Exon 1 of 8	NP_003367.4
	VEGFA	NM_001025366.3		c.64C>T	p.Arg22Trp	missense	Exon 1 of 8	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.64C>T	p.Arg22Trp	missense	Exon 1 of 8	NP_001020538.2	P15692-16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.64C>T	p.Arg22Trp	missense	Exon 1 of 8	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.64C>T	p.Arg22Trp	missense	Exon 1 of 8	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.64C>T	p.Arg22Trp	missense	Exon 1 of 7	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000276 AC: 23 AN: 83328 AF XY: 0.000189

Gnomad AFR exome AF: 0.00422

Gnomad AMR exome AF: 0.000815

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 142 AN: 1329860 Hom.: 2 Cov.: 36 AF XY: 0.000108 AC XY: 71 AN XY: 656110

African (AFR) AF: 0.00246 AC: 65 AN: 26416

American (AMR) AF: 0.000337 AC: 8 AN: 23764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21866

East Asian (EAS) AF: 0.00 AC: 0 AN: 30302

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43322

Middle Eastern (MID) AF: 0.000935 AC: 4 AN: 4278

European-Non Finnish (NFE) AF: 0.0000436 AC: 46 AN: 1055734

Other (OTH) AF: 0.000328 AC: 18 AN: 54946

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.000727 AC XY: 54 AN XY: 74328

African (AFR) AF: 0.00193 AC: 80 AN: 41448

American (AMR) AF: 0.00124 AC: 19 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000520 Hom.: 1

Bravo AF: 0.000620

ExAC AF: 0.0000549 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.043
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.051
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	P
MutPred		0.38		Loss of disorder (P = 0.0551)
MVP		0.23
ClinPred		0.069	T
GERP RS		-0.65
PromoterAI		-0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.14

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: rs764480708; hg19: chr6-43738507; COSMIC: COSV57878925; COSMIC: COSV57878925;