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rs758166016

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002506.3(NGF):​c.539G>A​(p.Arg180Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NGF
NM_002506.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.766
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-AS1 (HGNC:53922): (NGF antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a disulfide_bond (size 50) in uniprot entity NGF_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002506.3
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.12671342).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NGFNM_002506.3 linkuse as main transcriptc.539G>A p.Arg180Gln missense_variant 3/3 ENST00000369512.3
NGF-AS1NR_157569.1 linkuse as main transcriptn.207+3017C>T intron_variant, non_coding_transcript_variant
NGFXM_011541518.3 linkuse as main transcriptc.704G>A p.Arg235Gln missense_variant 3/3
NGFXM_006710663.4 linkuse as main transcriptc.539G>A p.Arg180Gln missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NGFENST00000369512.3 linkuse as main transcriptc.539G>A p.Arg180Gln missense_variant 3/31 NM_002506.3 P1
NGF-AS1ENST00000425449.1 linkuse as main transcriptn.207+3017C>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000460
AC:
7
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251492
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461892
Hom.:
0
Cov.:
30
AF XY:
0.0000165
AC XY:
12
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000460
AC:
7
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000378
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital sensory neuropathy with selective loss of small myelinated fibers Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeFeb 24, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 180 of the NGF protein (p.Arg180Gln). This variant is present in population databases (rs758166016, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NGF-related conditions. ClinVar contains an entry for this variant (Variation ID: 576877). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 16, 2020The p.R180Q variant (also known as c.539G>A), located in coding exon 1 of the NGF gene, results from a G to A substitution at nucleotide position 539. The arginine at codon 180 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.25
N
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.25
T
PROVEAN
Uncertain
-2.5
N
REVEL
Benign
0.14
Sift
Uncertain
0.021
D
Sift4G
Uncertain
0.025
D
Polyphen
0.048
B
Vest4
0.17
MVP
0.58
MPC
0.39
ClinPred
0.074
T
GERP RS
2.6
Varity_R
0.43
gMVP
0.68

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.

Other links and lift over

dbSNP: rs758166016; hg19: chr1-115828878; API