Genetic Variant VGF:p.Ala496Thr (chr7-101163358-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003378.4(VGF):c.1486G>A(p.Ala496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000059 in 1,356,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. A496V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 18)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VGF
NM_003378.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.586

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11369982).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003378.4. 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
	VGF	NM_003378.4	MANE Select	c.1486G>A	p.Ala496Thr	missense	Exon 2 of 2	NP_003369.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VGF	ENST00000249330.3	TSL:1 MANE Select	c.1486G>A	p.Ala496Thr	missense	Exon 2 of 2	ENSP00000249330.2	O15240
VGF	ENST00000445482.2	TSL:5	c.1486G>A	p.Ala496Thr	missense	Exon 2 of 2	ENSP00000400884.2	O15240
VGF	ENST00000970416.1		c.1486G>A	p.Ala496Thr	missense	Exon 2 of 2	ENSP00000640475.1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

113128

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:

0.000260

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000185

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000813

AC:

AN:

122932

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000215

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000590

AC:

AN:

1356580

Hom.:

Cov.:

AF XY:

0.00000300

AC XY:

AN XY:

665756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31286

American (AMR)

AF:

0.0000551

AC:

AN:

36276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23588

East Asian (EAS)

AF:

0.00

AC:

AN:

35970

South Asian (SAS)

AF:

0.00

AC:

AN:

75928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3930

European-Non Finnish (NFE)

AF:

0.00000566

AC:

AN:

1060342

Other (OTH)

AF:

0.00

AC:

AN:

56396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000177

AC:

AN:

113128

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

54252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28576

American (AMR)

AF:

0.00

AC:

AN:

10648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2890

East Asian (EAS)

AF:

0.000260

AC:

AN:

3848

South Asian (SAS)

AF:

0.00

AC:

AN:

3570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

54108

Other (OTH)

AF:

0.00

AC:

AN:

1456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.59

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

REVEL

Benign

0.041

Sift

Uncertain

0.027

Sift4G

Uncertain

0.053

Polyphen

0.042

Vest4

0.11

MutPred

0.14

Gain of relative solvent accessibility (P = 0.0023)

MVP

0.043

MPC

0.65

ClinPred

0.16

GERP RS

4.4

Varity_R

0.18

gMVP

0.065

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over