rs6330

Positions:

chr1-115286692-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002506.3(NGF):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,613,944 control chromosomes in the GnomAD database, including 146,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10911 hom., cov: 33)

Exomes 𝑓: 0.42 ( 135951 hom. )

Consequence

NGF
NM_002506.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.79

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=0.002656579).

BP6

Variant 1-115286692-G-A is Benign according to our data. Variant chr1-115286692-G-A is described in ClinVar as [Benign]. Clinvar id is 291993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115286692-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NGF	NM_002506.3 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	3/3	ENST00000369512.3
NGF-AS1	NR_157569.1 linkuse as main transcript	n.207+3452G>A		intron_variant, non_coding_transcript_variant
NGF	XM_011541518.3 linkuse as main transcript	c.269C>T	p.Ala90Val	missense_variant	3/3
NGF	XM_006710663.4 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NGF	ENST00000369512.3 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	3/3	1	NM_002506.3	P1
NGF-AS1	ENST00000425449.1 linkuse as main transcript	n.207+3452G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.356

AC:

54071

AN:

152008

Hom.:

10904

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.477

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.395

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.221

Gnomad FIN

AF:

0.484

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.455

Gnomad OTH

AF:

0.382

GnomAD3 exomes

AF:

0.370

AC:

92902

AN:

251406

Hom.:

18710

AF XY:

0.369

AC XY:

50196

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.346

Gnomad ASJ exome

AF:

0.391

Gnomad EAS exome

AF:

0.163

Gnomad SAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.481

Gnomad NFE exome

AF:

0.448

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.423

AC:

618017

AN:

1461818

Hom.:

135951

Cov.:

AF XY:

0.418

AC XY:

304116

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.180

Gnomad4 AMR exome

AF:

0.346

Gnomad4 ASJ exome

AF:

0.395

Gnomad4 EAS exome

AF:

0.175

Gnomad4 SAS exome

AF:

0.234

Gnomad4 FIN exome

AF:

0.473

Gnomad4 NFE exome

AF:

0.457

Gnomad4 OTH exome

AF:

0.394

GnomAD4 genome

AF:

0.356

AC:

54091

AN:

152126

Hom.:

10911

Cov.:

AF XY:

0.352

AC XY:

26201

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.358

Gnomad4 ASJ

AF:

0.395

Gnomad4 EAS

AF:

0.162

Gnomad4 SAS

AF:

0.221

Gnomad4 FIN

AF:

0.484

Gnomad4 NFE

AF:

0.455

Gnomad4 OTH

AF:

0.379

Alfa

AF:

0.423

Hom.:

36406

Bravo

AF:

0.341

TwinsUK

AF:

0.455

AC:

1688

ALSPAC

AF:

0.469

AC:

1806

ESP6500AA

AF:

0.207

AC:

911

ESP6500EA

AF:

0.452

AC:

3890

ExAC

AF:

0.365

AC:

44370

Asia WGS

AF:

0.182

AC:

637

AN:

3478

EpiCase

AF:

0.444

EpiControl

AF:

0.442

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital sensory neuropathy with selective loss of small myelinated fibers

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 18763222, 22330829) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Benign

-0.10

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.25

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.68

REVEL

Benign

0.097

Sift

Uncertain

0.022

Sift4G

Benign

0.16

Polyphen

0.0020

Vest4

0.014

MPC

0.34

ClinPred

0.015

GERP RS

4.5

Varity_R

0.062

gMVP

0.57

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