rs11466111

Positions:

• chr1-115286557-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002506.3(NGF):​c.239G>A​(p.Arg80Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,614,182 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.015 (206 hom.)
• Consequence: NGF NM_002506.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.04

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009551585).
• BP6: Variant 1-115286557-C-T is Benign according to our data. Variant chr1-115286557-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 291991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115286557-C-T is described in Lovd as [Benign]. Variant chr1-115286557-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1751/152300) while in subpopulation NFE AF= 0.0179 (1221/68034). AF 95% confidence interval is 0.0171. There are 18 homozygotes in gnomad4. There are 815 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NGF	NM_002506.3	c.239G>A	p.Arg80Gln	missense_variant	3/3	ENST00000369512.3	NP_002497.2
NGF	XM_011541518.3	c.404G>A	p.Arg135Gln	missense_variant	3/3		XP_011539820.1
NGF	XM_006710663.4	c.239G>A	p.Arg80Gln	missense_variant	2/2		XP_006710726.1
NGF-AS1	NR_157569.1	n.207+3317C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NGF	ENST00000369512.3	c.239G>A	p.Arg80Gln	missense_variant	3/3	1	NM_002506.3	ENSP00000358525.2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1750 AN: 152182 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0104 AC: 2609 AN: 251144 Hom.: 22 AF XY: 0.0108 AC XY: 1460 AN XY: 135804

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.00336

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.00995

GnomAD4 exome AF: 0.0147 AC: 21482 AN: 1461882 Hom.: 206 Cov.: 30 AF XY: 0.0144 AC XY: 10442 AN XY: 727244

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00467

Gnomad4 ASJ exome AF: 0.00926

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.00323

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0115 AC: 1751 AN: 152300 Hom.: 18 Cov.: 32 AF XY: 0.0109 AC XY: 815 AN XY: 74456

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0149 Hom.: 23

Bravo AF: 0.0106

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.0108 AC: 1308

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital sensory neuropathy with selective loss of small myelinated fibers Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

NGF-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2020

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.19
MPC		1.2
ClinPred		0.050	T
GERP RS		5.1
Varity_R		0.55
gMVP		0.64

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: rs11466111; hg19: chr1-115829178; COSMIC: COSV65687443;