NM_003378.4:c.1573G>A

Variant names:

• chr7-101163271-C-T
• rs35400704
• NM_003378.4:c.1573G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003378.4(VGF):​c.1573G>A​(p.Glu525Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,358,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: VGF NM_003378.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• Publications: 4 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2826392).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VGF	NM_003378.4	MANE Select	c.1573G>A	p.Glu525Lys	missense	Exon 2 of 2	NP_003369.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VGF	ENST00000249330.3	TSL:1 MANE Select	c.1573G>A	p.Glu525Lys	missense	Exon 2 of 2	ENSP00000249330.2
	VGF	ENST00000445482.2	TSL:5	c.1573G>A	p.Glu525Lys	missense	Exon 2 of 2	ENSP00000400884.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1358558 Hom.: 0 Cov.: 33 AF XY: 0.00000150 AC XY: 1 AN XY: 668168

African (AFR) AF: 0.00 AC: 0 AN: 29146

American (AMR) AF: 0.00 AC: 0 AN: 30464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19932

East Asian (EAS) AF: 0.00 AC: 0 AN: 37500

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 71128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4792

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1067458

Other (OTH) AF: 0.00 AC: 0 AN: 55858

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.38
MutPred		0.21		Gain of methylation at E525 (P = 0.0017)
MVP		0.068
MPC		0.75
ClinPred		0.55	D
GERP RS		4.6
Varity_R		0.33
gMVP		0.20
Mutation Taster		=95/5	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: rs35400704; hg19: chr7-100806552; COSMIC: COSV99973099; COSMIC: COSV99973099;