rs3024998

Variant names:

• chr6-43777840-C-T
• rs3024998
• NM_003376.6:c.855+175C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-43777840-C-T
• chr6-43777840-C-G

Variant summary

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

The NM_003376.6(VEGFA):​c.855+175C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 694,248 control chromosomes in the GnomAD database, including 36,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (7816 hom., cov: 31)
  • Exomes 𝑓: 0.32 (28566 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.107
• Publications: 13 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]

VEGFA Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-43777840-C-T is Benign according to our data. Variant chr6-43777840-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003376.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.855+175C>T		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.855+175C>T		intron	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.855+175C>T		intron	N/A	NP_001020538.2	P15692-16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.855+175C>T		intron	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.855+175C>T		intron	N/A	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.855+175C>T		intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48524 AN: 151792 Hom.: 7811 Cov.: 31

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.347

GnomAD4 exome AF: 0.319 AC: 172932 AN: 542338 Hom.: 28566 Cov.: 7 AF XY: 0.317 AC XY: 89471 AN XY: 282230

African (AFR) AF: 0.335 AC: 4775 AN: 14256

American (AMR) AF: 0.345 AC: 6905 AN: 20016

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 6067 AN: 14268

East Asian (EAS) AF: 0.440 AC: 13830 AN: 31446

South Asian (SAS) AF: 0.274 AC: 13066 AN: 47758

European-Finnish (FIN) AF: 0.235 AC: 7008 AN: 29792

Middle Eastern (MID) AF: 0.382 AC: 1439 AN: 3766

European-Non Finnish (NFE) AF: 0.314 AC: 110416 AN: 351844

Other (OTH) AF: 0.323 AC: 9426 AN: 29192

GnomAD4 genome AF: 0.320 AC: 48543 AN: 151910 Hom.: 7816 Cov.: 31 AF XY: 0.315 AC XY: 23397 AN XY: 74232

African (AFR) AF: 0.331 AC: 13705 AN: 41412

American (AMR) AF: 0.343 AC: 5237 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3468

East Asian (EAS) AF: 0.416 AC: 2139 AN: 5140

South Asian (SAS) AF: 0.271 AC: 1303 AN: 4810

European-Finnish (FIN) AF: 0.230 AC: 2431 AN: 10560

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.313 AC: 21251 AN: 67926

Other (OTH) AF: 0.349 AC: 737 AN: 2112

Alfa AF: 0.306 Hom.: 1111

Bravo AF: 0.336

Asia WGS AF: 0.302 AC: 1049 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.3
DANN	Benign	0.65
PhyloP100		0.11
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
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: rs3024998; hg19: chr6-43745577; COSMIC: COSV57879506; COSMIC: COSV57879506;