7-101163358-C-A

Variant names:

• chr7-101163358-C-A
• NM_003378.4:c.1486G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003378.4(VGF):​c.1486G>T​(p.Ala496Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A496T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 18)
• Consequence: VGF NM_003378.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.586

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]

ACMG classification

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=0.11676711).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VGF	NM_003378.4	c.1486G>T	p.Ala496Ser	missense_variant	Exon 2 of 2	ENST00000249330.3	NP_003369.2
VGF	XM_005250561.6	c.1486G>T	p.Ala496Ser	missense_variant	Exon 2 of 2		XP_005250618.1
VGF	XM_011516549.4	c.1486G>T	p.Ala496Ser	missense_variant	Exon 3 of 3		XP_011514851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VGF	ENST00000249330.3	c.1486G>T	p.Ala496Ser	missense_variant	Exon 2 of 2	1	NM_003378.4	ENSP00000249330.2
VGF	ENST00000445482.2	c.1486G>T	p.Ala496Ser	missense_variant	Exon 2 of 2	5		ENSP00000400884.2

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1486G>T (p.A496S) alteration is located in exon 2 (coding exon 1) of the VGF gene. This alteration results from a G to T substitution at nucleotide position 1486, causing the alanine (A) at amino acid position 496 to be replaced by a serine (S). 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	0.092
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.39	.;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.032
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.078	T;T
Polyphen		0.081	B;B
Vest4		0.15
MutPred		0.15		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.043
MPC		0.61
ClinPred		0.28	T
GERP RS		4.4
Varity_R		0.20
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-100806639;