chr6-43780906-T-C

Position:

• chr6-43780906-T-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.1034+103T>C variant causes a intron 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 NM_003376.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01

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 (HGNC:):

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 6-43780906-T-C is Benign according to our data. Variant chr6-43780906-T-C is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.1034+103T>C		intron_variant		ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.1034+103T>C		intron_variant			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

GnomAD3 exomes AF: 0.978 AC: 245080 AN: 250640 Hom.: 119862 AF XY: 0.977 AC XY: 132456 AN XY: 135544

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 SAS exome AF: 0.990

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

Gnomad4 AFR exome AF: 0.995

Gnomad4 AMR exome AF: 0.985

Gnomad4 ASJ exome AF: 0.948

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.989

Gnomad4 FIN exome AF: 0.973

Gnomad4 NFE exome AF: 0.971

Gnomad4 OTH exome AF: 0.974

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

Gnomad4 AFR AF: 0.994

Gnomad4 AMR AF: 0.978

Gnomad4 ASJ AF: 0.951

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.990

Gnomad4 FIN AF: 0.975

Gnomad4 NFE AF: 0.971

Gnomad4 OTH AF: 0.970

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4

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: rs3025052; hg19: chr6-43748643;