chr7-101163376-G-A

Position:

• chr7-101163376-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003378.4(VGF):​c.1468C>T​(p.Pro490Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,427,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: VGF NM_003378.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31776246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VGF	NM_003378.4	c.1468C>T	p.Pro490Ser	missense_variant	2/2	ENST00000249330.3	NP_003369.2
VGF	XM_005250561.6	c.1468C>T	p.Pro490Ser	missense_variant	2/2		XP_005250618.1
VGF	XM_011516549.4	c.1468C>T	p.Pro490Ser	missense_variant	3/3		XP_011514851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VGF	ENST00000249330.3	c.1468C>T	p.Pro490Ser	missense_variant	2/2	1	NM_003378.4	ENSP00000249330.2
VGF	ENST00000445482.2	c.1468C>T	p.Pro490Ser	missense_variant	2/2	5		ENSP00000400884.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427496 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 708298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000230

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.1468C>T (p.P490S) 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 1468, causing the proline (P) at amino acid position 490 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	0.22
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	0.096
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.55	.;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.96	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.30	T;T
Polyphen		0.74	P;P
Vest4		0.37
MutPred		0.20		Gain of phosphorylation at P490 (P = 0.0033);Gain of phosphorylation at P490 (P = 0.0033);
MVP		0.30
MPC		0.67
ClinPred		0.60	D
GERP RS		4.4
Varity_R		0.33
gMVP		0.13

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: chr7-100806657;