7-101163366-G-C

Position:

chr7-101163366-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000249330.3(VGF):c.1478C>G(p.Pro493Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 149,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P493H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VGF
ENST00000249330.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.118

Variant links:

Genes affected

VGF (HGNC:12684): (VGF nerve growth factor inducible) This gene is specifically expressed in a subpopulation of neuroendocrine cells, and is upregulated by nerve growth factor. The structural organization of this gene is similar to that of the rat gene, and both the translated and the untranslated regions show a high degree of sequence similarity to the rat gene. The encoded secretory protein also shares similarities with the secretogranin/chromogranin family, however, its exact function is not known. [provided by RefSeq, Jul 2008]

VGF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1510059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VGF	NM_003378.4 linkuse as main transcript	c.1478C>G	p.Pro493Arg	missense_variant	2/2	ENST00000249330.3	NP_003369.2	O15240
VGF	XM_005250561.6 linkuse as main transcript	c.1478C>G	p.Pro493Arg	missense_variant	2/2		XP_005250618.1	O15240
VGF	XM_011516549.4 linkuse as main transcript	c.1478C>G	p.Pro493Arg	missense_variant	3/3		XP_011514851.1	O15240

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VGF	ENST00000249330.3 linkuse as main transcript	c.1478C>G	p.Pro493Arg	missense_variant	2/2	1	NM_003378.4	ENSP00000249330.2		O15240
VGF	ENST00000445482.2 linkuse as main transcript	c.1478C>G	p.Pro493Arg	missense_variant	2/2	5		ENSP00000400884.2		O15240

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

149624

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000597

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

165726

Hom.:

AF XY:

0.0000220

AC XY:

AN XY:

90968

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000684

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000580

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000179

AC:

AN:

1393318

Hom.:

Cov.:

AF XY:

0.0000131

AC XY:

AN XY:

687340

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000744

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

149624

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

72920

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000597

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2024

The c.1478C>G (p.P493R) alteration is located in exon 2 (coding exon 1) of the VGF gene. This alteration results from a C to G substitution at nucleotide position 1478, causing the proline (P) at amino acid position 493 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.48

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.41

.;T

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

0.87

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.075

Sift

Uncertain

0.018

D;D

Sift4G

Benign

0.63

T;T

Polyphen

0.34

B;B

Vest4

0.21

MutPred

0.15

Loss of glycosylation at P493 (P = 0.0076);Loss of glycosylation at P493 (P = 0.0076);

MVP

0.043

MPC

0.71

ClinPred

0.094

GERP RS

3.5

Varity_R

0.13

gMVP

0.096

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over