rs3024997

chr6-43777370-G-Achr6-43777370-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003376.6(VEGFA):c.659-99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,383,676 control chromosomes in the GnomAD database, including 71,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (7692 hom., cov: 32)
  • Exomes 𝑓: 0.32 (63634 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.58

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]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-43777370-G-A is Benign according to our data. Variant chr6-43777370-G-A is described in ClinVar as [Benign]. Clinvar id is 1233590.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFA	NM_003376.6	c.659-99G>A		intron_variant		ENST00000672860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFA	ENST00000672860.3	c.659-99G>A		intron_variant			NM_003376.6

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48185 AN: 152014 Hom.: 7683 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.318 AC: 391233 AN: 1231544 Hom.: 63634 Cov.: 17 AF XY: 0.317 AC XY: 196645 AN XY: 621126

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.411

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.271

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.318

GnomAD4 genome AF: 0.317 AC: 48206 AN: 152132 Hom.: 7692 Cov.: 32 AF XY: 0.313 AC XY: 23246 AN XY: 74350

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.345

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.348

Alfa AF: 0.316 Hom.: 1934

Bravo AF: 0.333

Asia WGS AF: 0.303 AC: 1054 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.026
Dann	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs3024997; hg19: chr6-43745107; COSMIC: COSV57879996; COSMIC: COSV57879996;