Variant 7-101163309-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003378.4(VGF):c.1535C>T(p.Ala512Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,443,136 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 22)

Exomes 𝑓: 0.000034 ( 2 hom. )

Consequence

VGF
NM_003378.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.802

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020457804).

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VGF	NM_003378.4 linkuse as main transcript	c.1535C>T	p.Ala512Val	missense_variant	2/2	ENST00000249330.3	NP_003369.2
VGF	XM_005250561.6 linkuse as main transcript	c.1535C>T	p.Ala512Val	missense_variant	2/2		XP_005250618.1
VGF	XM_011516549.4 linkuse as main transcript	c.1535C>T	p.Ala512Val	missense_variant	3/3		XP_011514851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VGF	ENST00000249330.3 linkuse as main transcript	c.1535C>T	p.Ala512Val	missense_variant	2/2	1	NM_003378.4	ENSP00000249330	P1
VGF	ENST00000445482.2 linkuse as main transcript	c.1535C>T	p.Ala512Val	missense_variant	2/2	5		ENSP00000400884	P1

Frequencies

GnomAD3 genomes

AF:

0.00000683

AC:

AN:

146420

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:

0.000223

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

73748

Hom.:

AF XY:

0.0000257

AC XY:

AN XY:

38854

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 SAS exome

AF:

0.000575

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000339

AC:

AN:

1296716

Hom.:

Cov.:

AF XY:

0.0000443

AC XY:

AN XY:

632038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000644

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.63e-7

Gnomad4 OTH exome

AF:

0.0000186

GnomAD4 genome

AF:

0.00000683

AC:

AN:

146420

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71292

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:

0.000223

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000425

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

Dec 28, 2023

The c.1535C>T (p.A512V) alteration is located in exon 2 (coding exon 1) of the VGF gene. This alteration results from a C to T substitution at nucleotide position 1535, causing the alanine (A) at amino acid position 512 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

6.7

DANN

Benign

0.96

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.38

.;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.050

Sift

Benign

0.036

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.0

B;B

Vest4

0.084

MutPred

0.11

Gain of catalytic residue at A512 (P = 0.0373);Gain of catalytic residue at A512 (P = 0.0373);

MVP

0.043

MPC

0.66

ClinPred

0.018

GERP RS

-0.061

Varity_R

0.044

gMVP

0.051

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