1-115286113-GCC-G

Variant names:

• chr1-115286113-GCC-G
• rs1571069258
• NM_002506.3:c.681_682delGG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_002506.3(NGF):​c.681_682delGG​(p.Ala228LeufsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. T227T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NGF NM_002506.3 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.54
• Publications: 1 publications found

Genes affected

NGF (HGNC:7808): (nerve growth factor) This gene is a member of the NGF-beta family and encodes a secreted protein which homodimerizes and is incorporated into a larger complex. This protein has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy, type 5 (HSAN5), and dysregulation of this gene's expression is associated with allergic rhinitis. [provided by RefSeq, Jul 2008]

NGF-AS1 (HGNC:53922): (NGF antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.062 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGF	NM_002506.3	c.681_682delGG	p.Ala228LeufsTer43	frameshift_variant	Exon 3 of 3	ENST00000369512.3	NP_002497.2
NGF	NM_001437545.1	c.681_682delGG	p.Ala228LeufsTer43	frameshift_variant	Exon 2 of 2		NP_001424474.1
NGF	XM_011541518.3	c.846_847delGG	p.Ala283LeufsTer43	frameshift_variant	Exon 3 of 3		XP_011539820.1
NGF-AS1	NR_157569.1	n.207+2874_207+2875delCC		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGF	ENST00000369512.3	c.681_682delGG	p.Ala228LeufsTer43	frameshift_variant	Exon 3 of 3	1	NM_002506.3	ENSP00000358525.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:1

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Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

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: rs1571069258; hg19: chr1-115828734;