rs1193726870

Variant names:

• chr6-43771041-G-A
• rs1193726870
• NM_003376.6:c.335G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-43771041-G-A
• chr6-43771041-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003376.6(VEGFA):​c.335G>A​(p.Gly112Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,370,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G112V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: VEGFA NM_003376.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25568497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.335G>A	p.Gly112Asp	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.335G>A	p.Gly112Asp	missense_variant	Exon 1 of 8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1370822 Hom.: 0 Cov.: 36 AF XY: 0.00000148 AC XY: 1 AN XY: 675008

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000349 AC: 1 AN: 28670

American (AMR) AF: 0.00 AC: 0 AN: 33702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24062

East Asian (EAS) AF: 0.00 AC: 0 AN: 33210

South Asian (SAS) AF: 0.00 AC: 0 AN: 76290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067124

Other (OTH) AF: 0.00 AC: 0 AN: 56752

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;T;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.79	N;.;N;N;.;.;.;.;.;N;N;.;N;N;N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D;.;D;D;.;.;.;.;.;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D;.;D;.;D;D;D;D;D;D
Polyphen		0.93, 1.0, 1.0	.;.;.;.;P;D;.;D;D;.;.;.;.;.;.
MutPred		0.28		Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);Gain of ubiquitination at K115 (P = 0.0395);
MVP		0.12
ClinPred		0.90	D
GERP RS		3.6
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
gMVP		0.21
Mutation Taster		=261/39	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: rs1193726870; hg19: chr6-43738778;