rs1355913467

Variant names:

• chr6-43770804-G-T
• rs1355913467
• NM_003376.6:c.98G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003376.6(VEGFA):​c.98G>T​(p.Gly33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,356,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: VEGFA NM_003376.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• Publications: 5 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]

ENSG00000272114 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063699335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.98G>T	p.Gly33Val	missense_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.98G>T	p.Gly33Val	missense_variant	Exon 1 of 8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000281 AC: 3 AN: 106726 AF XY: 0.00

Gnomad AFR exome AF: 0.000596

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000520

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1356224 Hom.: 0 Cov.: 36 AF XY: 0.00000150 AC XY: 1 AN XY: 668682

African (AFR) AF: 0.00 AC: 0 AN: 27306

American (AMR) AF: 0.00 AC: 0 AN: 29992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23784

East Asian (EAS) AF: 0.00 AC: 0 AN: 31066

South Asian (SAS) AF: 0.00 AC: 0 AN: 74456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1062950

Other (OTH) AF: 0.00 AC: 0 AN: 55936

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microvascular complications of diabetes, susceptibility to, 1 Uncertain:1

Jun 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T;.;.;T;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.064	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.46	N;.;N;N;.;.;.;.;.;N;N;.;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.040	D;.;D;D;.;.;.;.;.;D;D;.;D;D;D
Sift4G	Uncertain	0.0060	D;.;D;D;D;D;.;D;.;D;D;D;D;D;D
Polyphen		0.49, 0.28, 0.062, 0.13	.;.;.;.;P;B;.;B;B;.;.;.;.;.;.
MutPred		0.18		Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);Loss of catalytic residue at G33 (P = 0.0662);
MVP		0.10
ClinPred		0.32	T
GERP RS		2.9
PromoterAI		-0.32	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.061
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1355913467; hg19: chr6-43738541;