6-43770744-G-T

Variant names:

• chr6-43770744-G-T
• rs942729487
• NM_003376.6:c.38G>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.38G>T​(p.Ser13Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: VEGFA NM_003376.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• 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]

ENSG00000272114 (HGNC:):

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=0.21247074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.38G>T	p.Ser13Ile	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.38G>T	p.Ser13Ile	missense_variant	Exon 1 of 8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370134 Hom.: 0 Cov.: 36 AF XY: 0.00000147 AC XY: 1 AN XY: 679686

African (AFR) AF: 0.00 AC: 0 AN: 28190

American (AMR) AF: 0.00 AC: 0 AN: 31058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23832

East Asian (EAS) AF: 0.00 AC: 0 AN: 32314

South Asian (SAS) AF: 0.00 AC: 0 AN: 75860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5026

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077032

Other (OTH) AF: 0.0000177 AC: 1 AN: 56524

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38G>T (p.S13I) alteration is located in exon 1 (coding exon 1) of the VEGFA gene. This alteration results from a G to T substitution at nucleotide position 38, causing the serine (S) at amino acid position 13 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;T;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.69	N;.;N;N;.;.;.;.;.;N;N;.;N;N;N
REVEL	Benign	0.089
Sift	Pathogenic	0.0	D;.;D;D;.;.;.;.;.;D;D;.;D;D;D
Sift4G	Uncertain	0.013	D;.;D;D;D;D;.;D;.;D;D;D;D;D;D
Polyphen		1.0, 0.99, 1.0	.;.;.;.;D;D;.;D;D;.;.;.;.;.;.
MutPred		0.26		Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);Gain of catalytic residue at S13 (P = 0.0082);
MVP		0.48
ClinPred		0.89	D
GERP RS		2.2
PromoterAI		-0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.29
Mutation Taster		=99/1	polymorphism

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: rs942729487; hg19: chr6-43738481;