chr11-64237220-C-T

Variant names:

• chr11-64237220-C-T
• rs12366035
• NM_003377.5:c.408C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003377.5(VEGFB):​c.408C>T​(p.Asp136Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,554,184 control chromosomes in the GnomAD database, including 65,282 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4045 hom., cov: 28)
  • Exomes 𝑓: 0.28 (61237 hom.)
• Consequence: VEGFB NM_003377.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.4939
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.41
• Publications: 24 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-64237220-C-T is Benign according to our data. Variant chr11-64237220-C-T is described in ClinVar as Benign. ClinVar VariationId is 769376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.41 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4045 gene

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.408C>T	p.Asp136Asp	splice_region synonymous	Exon 5 of 7	NP_003368.1	Q7LAP4
	VEGFB	NM_001243733.2		c.408C>T	p.Asp136Asp	splice_region synonymous	Exon 5 of 7	NP_001230662.1	P49765-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFB	ENST00000309422.7	TSL:1 MANE Select	c.408C>T	p.Asp136Asp	splice_region synonymous	Exon 5 of 7	ENSP00000311127.2	P49765-1
	VEGFB	ENST00000426086.3	TSL:1	c.408C>T	p.Asp136Asp	splice_region synonymous	Exon 5 of 7	ENSP00000401550.2	P49765-2
	VEGFB	ENST00000970134.1		c.459C>T	p.Asp153Asp	splice_region synonymous	Exon 5 of 7	ENSP00000640193.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 29665 AN: 147180 Hom.: 4047 Cov.: 28

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.230 AC: 54906 AN: 238434 AF XY: 0.245

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.276 AC: 388000 AN: 1406888 Hom.: 61237 Cov.: 33 AF XY: 0.279 AC XY: 194764 AN XY: 698190

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0400 AC: 1325 AN: 33092

American (AMR) AF: 0.105 AC: 4487 AN: 42634

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 5625 AN: 24862

East Asian (EAS) AF: 0.108 AC: 4207 AN: 39064

South Asian (SAS) AF: 0.294 AC: 22922 AN: 78004

European-Finnish (FIN) AF: 0.254 AC: 13080 AN: 51420

Middle Eastern (MID) AF: 0.284 AC: 1580 AN: 5562

European-Non Finnish (NFE) AF: 0.298 AC: 320112 AN: 1074292

Other (OTH) AF: 0.253 AC: 14662 AN: 57958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.201 AC: 29652 AN: 147296 Hom.: 4045 Cov.: 28 AF XY: 0.199 AC XY: 14266 AN XY: 71662

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0503 AC: 2060 AN: 40988

American (AMR) AF: 0.158 AC: 2339 AN: 14796

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 767 AN: 3384

East Asian (EAS) AF: 0.110 AC: 554 AN: 5014

South Asian (SAS) AF: 0.286 AC: 1300 AN: 4552

European-Finnish (FIN) AF: 0.237 AC: 2302 AN: 9698

Middle Eastern (MID) AF: 0.259 AC: 75 AN: 290

European-Non Finnish (NFE) AF: 0.297 AC: 19543 AN: 65694

Other (OTH) AF: 0.211 AC: 422 AN: 2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.239 Hom.: 1733

Bravo AF: 0.196

Asia WGS AF: 0.177 AC: 616 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		1.4
PromoterAI		-0.046	Neutral
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.49
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.080		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: rs12366035; hg19: chr11-64004692; COSMIC: COSV58535927; COSMIC: COSV58535927;