chr7-101163289-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_003378.4(VGF):​c.1555G>A​(p.Glu519Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000402 in 1,243,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: VGF NM_003378.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18258598).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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>A	p.Glu519Lys	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>A	p.Glu519Lys	missense	Exon 2 of 2	ENSP00000249330.2	O15240
	VGF	ENST00000445482.2	TSL:5	c.1555G>A	p.Glu519Lys	missense	Exon 2 of 2	ENSP00000400884.2	O15240
	VGF	ENST00000970416.1		c.1555G>A	p.Glu519Lys	missense	Exon 2 of 2	ENSP00000640475.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.00 AC: 0 AN: 142420 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000402 AC: 5 AN: 1243006 Hom.: 0 Cov.: 34 AF XY: 0.00000328 AC XY: 2 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: 0.000107 AC: 3 AN: 27940

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

European-Non Finnish (NFE) AF: 0.00000201 AC: 2 AN: 995870

Other (OTH) AF: 0.00 AC: 0 AN: 48794

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.15
Sift	Benign	0.043	D
Sift4G	Benign	0.30	T
Polyphen		0.30	B
Vest4		0.27
MutPred		0.061		Gain of ubiquitination at E519 (P = 0.0051)
MVP		0.043
MPC		0.75
ClinPred		0.28	T
GERP RS		3.7
Varity_R		0.15
gMVP		0.20
Mutation Taster		=100/0	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;