7-101163289-C-G

Variant names:

• chr7-101163289-C-G
• rs1189627973
• NM_003378.4:c.1555G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003378.4(VGF):​c.1555G>C​(p.Glu519Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,370,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E519K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000078 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: VGF NM_003378.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11368415).

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.1555G>C	p.Glu519Gln	missense	Exon 2 of 2	NP_003369.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VGF	ENST00000249330.3	TSL:1 MANE Select	c.1555G>C	p.Glu519Gln	missense	Exon 2 of 2	ENSP00000249330.2	O15240
	VGF	ENST00000445482.2	TSL:5	c.1555G>C	p.Glu519Gln	missense	Exon 2 of 2	ENSP00000400884.2	O15240
	VGF	ENST00000970416.1		c.1555G>C	p.Glu519Gln	missense	Exon 2 of 2	ENSP00000640475.1

Frequencies

GnomAD3 genomes AF: 0.00000784 AC: 1 AN: 127528 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

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: 0.0000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000161 AC: 2 AN: 1243006 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 609972

African (AFR) AF: 0.00 AC: 0 AN: 26180

American (AMR) AF: 0.00 AC: 0 AN: 26658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16210

East Asian (EAS) AF: 0.00 AC: 0 AN: 28464

South Asian (SAS) AF: 0.00 AC: 0 AN: 69158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3732

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 995870

Other (OTH) AF: 0.0000205 AC: 1 AN: 48794

GnomAD4 genome AF: 0.00000784 AC: 1 AN: 127528 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 60664

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33958

American (AMR) AF: 0.00 AC: 0 AN: 11602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3244

East Asian (EAS) AF: 0.00 AC: 0 AN: 3760

South Asian (SAS) AF: 0.00 AC: 0 AN: 3676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.0000162 AC: 1 AN: 61598

Other (OTH) AF: 0.00 AC: 0 AN: 1712

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Benign	0.056	T
Sift4G	Benign	0.32	T
Polyphen		0.0050	B
Vest4		0.17
MutPred		0.045		Gain of glycosylation at P515 (P = 0.2914)
MVP		0.043
MPC		0.66
ClinPred		0.17	T
GERP RS		3.7
Varity_R		0.16
gMVP		0.14
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1189627973; hg19: chr7-100806570;