6-43780906-T-C

Variant names:

• chr6-43780906-T-C
• rs3025052
• ENST00000480614.1:n.6589T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000480614.1(VEGFA):​n.6589T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.974 in 1,612,486 control chromosomes in the GnomAD database, including 765,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.98 (73054 hom., cov: 30)
  • Exomes 𝑓: 0.97 (692581 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-43780906-T-C is Benign according to our data. Variant chr6-43780906-T-C is described in ClinVar as Benign. ClinVar VariationId is 1278094.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.1034+103T>C		intron_variant	Intron 6 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.1034+103T>C		intron_variant	Intron 6 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.980 AC: 149012 AN: 152116 Hom.: 72995 Cov.: 30

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.990

Gnomad FIN AF: 0.975

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.970

GnomAD2 exomes AF: 0.978 AC: 245080 AN: 250640 AF XY: 0.977

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.986

Gnomad ASJ exome AF: 0.948

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.974

Gnomad NFE exome AF: 0.970

Gnomad OTH exome AF: 0.973

GnomAD4 exome AF: 0.974 AC: 1422085 AN: 1460252 Hom.: 692581 Cov.: 45 AF XY: 0.974 AC XY: 707405 AN XY: 726446

African (AFR) AF: 0.995 AC: 33253 AN: 33424

American (AMR) AF: 0.985 AC: 44049 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 24776 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39687 AN: 39700

South Asian (SAS) AF: 0.989 AC: 85271 AN: 86190

European-Finnish (FIN) AF: 0.973 AC: 51785 AN: 53206

Middle Eastern (MID) AF: 0.967 AC: 4575 AN: 4730

European-Non Finnish (NFE) AF: 0.971 AC: 1079981 AN: 1111904

Other (OTH) AF: 0.974 AC: 58708 AN: 60252

GnomAD4 genome AF: 0.980 AC: 149130 AN: 152234 Hom.: 73054 Cov.: 30 AF XY: 0.980 AC XY: 72928 AN XY: 74434

African (AFR) AF: 0.994 AC: 41298 AN: 41528

American (AMR) AF: 0.978 AC: 14955 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3301 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5168 AN: 5168

South Asian (SAS) AF: 0.990 AC: 4778 AN: 4824

European-Finnish (FIN) AF: 0.975 AC: 10345 AN: 10606

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 66057 AN: 68026

Other (OTH) AF: 0.970 AC: 2049 AN: 2112

Alfa AF: 0.970 Hom.: 43927

Bravo AF: 0.980

Asia WGS AF: 0.996 AC: 3462 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs3025052; hg19: chr6-43748643;