NM_002506.3:c.680_682delCGGinsA

Variant names:

• chr1-115286114-CCG-T
• rs2101018240
• NM_002506.3:c.680_682delCGGinsA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_002506.3(NGF):​c.680_682delCGGinsA​(p.Thr227AsnfsTer44) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). 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, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.80
• Publications: 0 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: Likely_pathogenic. The variant received 6 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 0.0634 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-115286114-CCG-T is Pathogenic according to our data. Variant chr1-115286114-CCG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29802.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002506.3. 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
	NGF	NM_002506.3	MANE Select	c.680_682delCGGinsA	p.Thr227AsnfsTer44	frameshift missense	Exon 3 of 3	NP_002497.2	P01138
	NGF	NM_001437545.1		c.680_682delCGGinsA	p.Thr227AsnfsTer44	frameshift missense	Exon 2 of 2	NP_001424474.1
	NGF-AS1	NR_157569.1		n.207+2874_207+2876delCCGinsT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGF	ENST00000369512.3	TSL:1 MANE Select	c.680_682delCGGinsA	p.Thr227AsnfsTer44	frameshift missense	Exon 3 of 3	ENSP00000358525.2	P01138
	NGF	ENST00000675637.2		c.680_682delCGGinsA	p.Thr227AsnfsTer44	frameshift missense	Exon 2 of 2	ENSP00000502831.1	P01138
	NGF	ENST00000676038.2		c.680_682delCGGinsA	p.Thr227AsnfsTer44	frameshift missense	Exon 4 of 4	ENSP00000502380.1	P01138

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital sensory neuropathy with selective loss of small myelinated fibers (1)
1	-	-	Peripheral neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=3/197	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2101018240; hg19: chr1-115828735;