Variant 7-101163121-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000249330.3(VGF):c.1723C>T(p.His575Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,584,348 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

VGF
ENST00000249330.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.188

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09646082).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VGF	NM_003378.4 linkuse as main transcript	c.1723C>T	p.His575Tyr	missense_variant	2/2	ENST00000249330.3	NP_003369.2	O15240
VGF	XM_005250561.6 linkuse as main transcript	c.1723C>T	p.His575Tyr	missense_variant	2/2		XP_005250618.1	O15240
VGF	XM_011516549.4 linkuse as main transcript	c.1723C>T	p.His575Tyr	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.1723C>T	p.His575Tyr	missense_variant	2/2	1	NM_003378.4	ENSP00000249330.2		O15240
VGF	ENST00000445482.2 linkuse as main transcript	c.1723C>T	p.His575Tyr	missense_variant	2/2	5		ENSP00000400884.2		O15240

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.0000142

AC:

AN:

211472

Hom.:

AF XY:

0.00000853

AC XY:

AN XY:

117224

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000318

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000768

AC:

AN:

1432506

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

712528

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000240

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:

0.00000454

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.000481

Bravo

AF:

0.0000264

ExAC

AF:

0.0000167

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

Aug 17, 2022

The c.1723C>T (p.H575Y) 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 1723, causing the histidine (H) at amino acid position 575 to be replaced by a tyrosine (Y). 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

0.085

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.085

T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.47

.;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

0.95

N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.71

N;N

REVEL

Benign

0.16

Sift

Benign

0.20

T;T

Sift4G

Benign

0.80

T;T

Polyphen

0.0

B;B

Vest4

0.19

MutPred

0.090

Gain of phosphorylation at H575 (P = 0.0449);Gain of phosphorylation at H575 (P = 0.0449);

MVP

0.043

MPC

0.77

ClinPred

0.030

GERP RS

3.2

Varity_R

0.063

gMVP

0.18

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