7-101163337-C-T

Variant names:

• chr7-101163337-C-T
• rs1202377910
• NM_003378.4:c.1507G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003378.4(VGF):​c.1507G>A​(p.Val503Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. V503A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: VGF NM_003378.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.598

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050408095).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VGF	NM_003378.4	c.1507G>A	p.Val503Ile	missense_variant	Exon 2 of 2	ENST00000249330.3	NP_003369.2
VGF	XM_005250561.6	c.1507G>A	p.Val503Ile	missense_variant	Exon 2 of 2		XP_005250618.1
VGF	XM_011516549.4	c.1507G>A	p.Val503Ile	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.1507G>A	p.Val503Ile	missense_variant	Exon 2 of 2	1	NM_003378.4	ENSP00000249330.2
VGF	ENST00000445482.2	c.1507G>A	p.Val503Ile	missense_variant	Exon 2 of 2	5		ENSP00000400884.2

Frequencies

GnomAD3 genomes AF: 0.000554 AC: 6 AN: 10828 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000792

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000334

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000128 AC: 1 AN: 78386 Hom.: 0 AF XY: 0.0000243 AC XY: 1 AN XY: 41152

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: 0.0000856

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 8 AN: 237800 Hom.: 0 Cov.: 4 AF XY: 0.0000402 AC XY: 5 AN XY: 124292

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: 0.0000295

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000484

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000554 AC: 6 AN: 10832 Hom.: 0 Cov.: 0 AF XY: 0.000375 AC XY: 2 AN XY: 5332

Gnomad4 AFR AF: 0.000791

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000334

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1507G>A (p.V503I) alteration is located in exon 2 (coding exon 1) of the VGF gene. This alteration results from a G to A substitution at nucleotide position 1507, causing the valine (V) at amino acid position 503 to be replaced by an isoleucine (I). 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	0.090
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.092	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.44	.;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.10
Sift	Benign	0.23	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0030	B;B
Vest4		0.089
MutPred		0.081		Loss of methylation at R504 (P = 0.1041);Loss of methylation at R504 (P = 0.1041);
MVP		0.043
MPC		0.54
ClinPred		0.074	T
GERP RS		1.3
Varity_R		0.088
gMVP		0.050

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

Other links and lift over

dbSNP: rs1202377910; hg19: chr7-100806618;