rs11466111

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.04

Variant links:

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 links:

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

NGF-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
NGF	NM_002506.3 link	c.239G>A	p.Arg80Gln	missense_variant	Exon 3 of 3	ENST00000369512.3	NP_002497.2	P01138
NGF	XM_011541518.3 link	c.404G>A	p.Arg135Gln	missense_variant	Exon 3 of 3		XP_011539820.1	A0A346FYQ1
NGF	XM_006710663.4 link	c.239G>A	p.Arg80Gln	missense_variant	Exon 2 of 2		XP_006710726.1	P01138
NGF-AS1	NR_157569.1 link	n.207+3317C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGF	ENST00000369512.3 link	c.239G>A	p.Arg80Gln	missense_variant	Exon 3 of 3	1	NM_002506.3	ENSP00000358525.2		P01138

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1750

AN:

152182

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0108

AC XY:

1460

AN XY:

135804

show subpopulations

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.:

AF XY:

0.0144

AC XY:

10442

AN XY:

727244

show subpopulations

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.:

Cov.:

AF XY:

0.0109

AC XY:

815

AN XY:

74456

show subpopulations

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.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0108

AC:

1308

Asia WGS

AF:

0.00115

AC:

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

LINK: link

Submissions by phenotype

Congenital sensory neuropathy with selective loss of small myelinated fibers

Benign:5

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NGF-related disorder

Benign:1

Mar 18, 2020

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

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0096

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.3

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.22

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.057

Polyphen

1.0

Vest4

0.19

MPC

1.2

ClinPred

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over