Genetic Variant VEGFB:p.Thr74Ile (chr11-64235930-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003377.5(VEGFB):c.221C>T(p.Thr74Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,892 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T74S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VEGFB
NM_003377.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.66

Publications

0 publications found

Variant links:

Genes affected

VEGFB (HGNC:12681): (vascular endothelial growth factor B) This gene encodes a member of the PDGF (platelet-derived growth factor)/VEGF (vascular endothelial growth factor) family. The VEGF family members regulate the formation of blood vessels and are involved in endothelial cell physiology. This member is a ligand for VEGFR-1 (vascular endothelial growth factor receptor 1) and NRP-1 (neuropilin-1). Studies in mice showed that this gene was co-expressed with nuclear-encoded mitochondrial genes and the encoded protein specifically controlled endothelial uptake of fatty acids. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Sep 2011]

VEGFB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003377.5. 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
	VEGFB	NM_003377.5	MANE Select	c.221C>T	p.Thr74Ile	missense	Exon 3 of 7	NP_003368.1	Q7LAP4
	VEGFB	NM_001243733.2		c.221C>T	p.Thr74Ile	missense	Exon 3 of 7	NP_001230662.1	P49765-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VEGFB	ENST00000309422.7	TSL:1 MANE Select	c.221C>T	p.Thr74Ile	missense	Exon 3 of 7	ENSP00000311127.2	P49765-1
VEGFB	ENST00000426086.3	TSL:1	c.221C>T	p.Thr74Ile	missense	Exon 3 of 7	ENSP00000401550.2	P49765-2
VEGFB	ENST00000970134.1		c.272C>T	p.Thr91Ile	missense	Exon 3 of 7	ENSP00000640193.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247788

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111852

Other (OTH)

AF:

0.00

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.79

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.5

PhyloP100

2.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.8

REVEL

Benign

0.16

Sift

Benign

0.034

Sift4G

Uncertain

0.041

Polyphen

1.0

Vest4

0.57

MutPred

0.48

Loss of catalytic residue at T74 (P = 0.0239)

MVP

0.37

MPC

0.17

ClinPred

0.79

GERP RS

4.9

Varity_R

0.40

gMVP

0.40

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over