chr1-115286742-C-T

Variant names:

• chr1-115286742-C-T
• rs6325
• NM_002506.3:c.54G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002506.3(NGF):​c.54G>A​(p.Ala18Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00693 in 1,614,086 control chromosomes in the GnomAD database, including 724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (364 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (360 hom.)
• Consequence: NGF NM_002506.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.59

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

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-115286742-C-T is Benign according to our data. Variant chr1-115286742-C-T is described in ClinVar as [Benign]. Clinvar id is 291994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115286742-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGF	NM_002506.3	c.54G>A	p.Ala18Ala	synonymous_variant	Exon 3 of 3	ENST00000369512.3	NP_002497.2
NGF	XM_011541518.3	c.219G>A	p.Ala73Ala	synonymous_variant	Exon 3 of 3		XP_011539820.1
NGF	XM_006710663.4	c.54G>A	p.Ala18Ala	synonymous_variant	Exon 2 of 2		XP_006710726.1
NGF-AS1	NR_157569.1	n.207+3502C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGF	ENST00000369512.3	c.54G>A	p.Ala18Ala	synonymous_variant	Exon 3 of 3	1	NM_002506.3	ENSP00000358525.2

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5667 AN: 152082 Hom.: 365 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.00968 AC: 2434 AN: 251488 Hom.: 175 AF XY: 0.00708 AC XY: 962 AN XY: 135920

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00377 AC: 5515 AN: 1461886 Hom.: 360 Cov.: 33 AF XY: 0.00317 AC XY: 2309 AN XY: 727246

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.0373 AC: 5671 AN: 152200 Hom.: 364 Cov.: 32 AF XY: 0.0351 AC XY: 2614 AN XY: 74394

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0197 Hom.: 95

Bravo AF: 0.0411

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital sensory neuropathy with selective loss of small myelinated fibers Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NGF-related disorder Benign:1

Dec 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs6325; hg19: chr1-115829363; COSMIC: COSV105300035;