4-176687827-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_005429.5(VEGFC):c.805G>A(p.Gly269Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000335 in 1,609,718 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: VEGFC NM_005429.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.19

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

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09688923).
• BP6: Variant 4-176687827-C-T is Benign according to our data. Variant chr4-176687827-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1686366.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFC	NM_005429.5	c.805G>A	p.Gly269Arg	missense_variant	5/7	ENST00000618562.2
HAFML	NR_183975.1	n.183-18076C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFC	ENST00000618562.2	c.805G>A	p.Gly269Arg	missense_variant	5/7	1	NM_005429.5	P1
HAFML	ENST00000509194.1	n.90-18076C>T		intron_variant, non_coding_transcript_variant		3
HAFML	ENST00000504017.5	n.140+8077C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000372 AC: 92 AN: 247444 Hom.: 0 AF XY: 0.000432 AC XY: 58 AN XY: 134268

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000412

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000265

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000524

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000336 AC: 490 AN: 1457408 Hom.: 2 Cov.: 30 AF XY: 0.000365 AC XY: 265 AN XY: 725204

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.000361

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000326

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000355

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74480

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000729 AC: 6

ExAC AF: 0.000447 AC: 54

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.805G>A (p.G269R) alteration is located in exon 5 (coding exon 5) of the VEGFC gene. This alteration results from a G to A substitution at nucleotide position 805, causing the glycine (G) at amino acid position 269 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.0066
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.46	T
Polyphen		0.36	B
Vest4		0.43
MutPred		0.17		Gain of glycosylation at T273 (P = 0.0522);
MVP		0.34
ClinPred		0.038	T
GERP RS		5.3
Varity_R		0.096
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs200182587; hg19: chr4-177608981;