chr6-43774222-T-C

Variant names:

• chr6-43774222-T-C
• rs3024989
• NM_003376.6:c.607-119T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001025366.3(VEGFA):​c.607-119T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,086,992 control chromosomes in the GnomAD database, including 20 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 0.0077 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (4 hom.)
• Consequence: VEGFA NM_001025366.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.578
• 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00767 (1168/152282) while in subpopulation AFR AF = 0.0262 (1088/41552). AF 95% confidence interval is 0.0249. There are 16 homozygotes in GnomAd4. There are 544 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1168 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025366.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.607-119T>C		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.607-119T>C		intron	N/A	NP_001020537.2
	VEGFA	NM_001025367.3		c.607-119T>C		intron	N/A	NP_001020538.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.607-119T>C		intron	N/A	ENSP00000500082.3
	VEGFA	ENST00000372055.9	TSL:1	c.607-119T>C		intron	N/A	ENSP00000361125.5
	VEGFA	ENST00000425836.9	TSL:1	c.607-119T>C		intron	N/A	ENSP00000388465.4

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1164 AN: 152164 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.000870 AC: 813 AN: 934710 Hom.: 4 Cov.: 13 AF XY: 0.000671 AC XY: 324 AN XY: 482668

African (AFR) AF: 0.0275 AC: 635 AN: 23072

American (AMR) AF: 0.00185 AC: 70 AN: 37752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22338

East Asian (EAS) AF: 0.00 AC: 0 AN: 35272

South Asian (SAS) AF: 0.0000690 AC: 5 AN: 72476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46870

Middle Eastern (MID) AF: 0.000601 AC: 2 AN: 3326

European-Non Finnish (NFE) AF: 0.00000768 AC: 5 AN: 650664

Other (OTH) AF: 0.00224 AC: 96 AN: 42940

GnomAD4 genome AF: 0.00767 AC: 1168 AN: 152282 Hom.: 16 Cov.: 32 AF XY: 0.00730 AC XY: 544 AN XY: 74476

African (AFR) AF: 0.0262 AC: 1088 AN: 41552

American (AMR) AF: 0.00425 AC: 65 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68012

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00718 Hom.: 1

Bravo AF: 0.00909

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.6
DANN	Benign	0.87
PhyloP100		-0.58
PromoterAI		-0.036	Neutral
Mutation Taster		=100/0	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: rs3024989; hg19: chr6-43741959;