4-176688049-G-C

Variant names:

• chr4-176688049-G-C
• rs13136065
• NM_005429.5:c.705-122C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005429.5(VEGFC):​c.705-122C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 387,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: VEGFC NM_005429.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.503
• Publications: 0 publications found

Genes affected

VEGFC (HGNC:12682): (vascular endothelial growth factor C) The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. The encoded protein promotes angiogenesis and endothelial cell growth, and can also affect the permeability of blood vessels. The proprotein is further cleaved into a fully processed form that can bind and activate VEGFR-2 and VEGFR-3 receptors. [provided by RefSeq, Apr 2014]

HAFML (HGNC:56694): (HuR (ELAVL1) associated fibroblast migratory lncRNA)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005429.5. 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
	VEGFC	NM_005429.5	MANE Select	c.705-122C>G		intron	N/A	NP_005420.1	P49767
	HAFML	NR_183975.1		n.183-17854G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFC	ENST00000618562.2	TSL:1 MANE Select	c.705-122C>G		intron	N/A	ENSP00000480043.1	P49767
	HAFML	ENST00000504017.6	TSL:2	n.243+8299G>C		intron	N/A
	HAFML	ENST00000509194.2	TSL:3	n.156-17854G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000258 AC: 1 AN: 387376 Hom.: 0 AF XY: 0.00000498 AC XY: 1 AN XY: 200838

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

African (AFR) AF: 0.00 AC: 0 AN: 9888

American (AMR) AF: 0.00 AC: 0 AN: 11564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11670

East Asian (EAS) AF: 0.00 AC: 0 AN: 26230

South Asian (SAS) AF: 0.00 AC: 0 AN: 25682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3304

European-Non Finnish (NFE) AF: 0.00000418 AC: 1 AN: 238954

Other (OTH) AF: 0.00 AC: 0 AN: 22698

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.0
DANN	Benign	0.57
PhyloP100		0.50

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: rs13136065; hg19: chr4-177609203;