rs6330

Variant names:

• chr1-115286692-G-A
• rs6330
• NM_002506.3:c.104C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.79
• Publications: 90 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 291993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002506.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGF	NM_002506.3	MANE Select	c.104C>T	p.Ala35Val	missense	Exon 3 of 3	NP_002497.2	P01138
	NGF	NM_001437545.1		c.104C>T	p.Ala35Val	missense	Exon 2 of 2	NP_001424474.1
	NGF-AS1	NR_157569.1		n.207+3452G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGF	ENST00000369512.3	TSL:1 MANE Select	c.104C>T	p.Ala35Val	missense	Exon 3 of 3	ENSP00000358525.2	P01138
	NGF	ENST00000675637.2		c.104C>T	p.Ala35Val	missense	Exon 2 of 2	ENSP00000502831.1	P01138
	NGF	ENST00000676038.2		c.104C>T	p.Ala35Val	missense	Exon 4 of 4	ENSP00000502380.1	P01138

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54071 AN: 152008 Hom.: 10904 Cov.: 33

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

GnomAD2 exomes AF: 0.370 AC: 92902 AN: 251406 AF XY: 0.369

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 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.: 65 AF XY: 0.418 AC XY: 304116 AN XY: 727208

African (AFR) AF: 0.180 AC: 6023 AN: 33480

American (AMR) AF: 0.346 AC: 15492 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10314 AN: 26136

East Asian (EAS) AF: 0.175 AC: 6940 AN: 39700

South Asian (SAS) AF: 0.234 AC: 20148 AN: 86258

European-Finnish (FIN) AF: 0.473 AC: 25247 AN: 53398

Middle Eastern (MID) AF: 0.320 AC: 1847 AN: 5768

European-Non Finnish (NFE) AF: 0.457 AC: 508199 AN: 1111962

Other (OTH) AF: 0.394 AC: 23807 AN: 60394

GnomAD4 genome AF: 0.356 AC: 54091 AN: 152126 Hom.: 10911 Cov.: 33 AF XY: 0.352 AC XY: 26201 AN XY: 74354

African (AFR) AF: 0.192 AC: 7960 AN: 41522

American (AMR) AF: 0.358 AC: 5477 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1370 AN: 3470

East Asian (EAS) AF: 0.162 AC: 834 AN: 5156

South Asian (SAS) AF: 0.221 AC: 1064 AN: 4824

European-Finnish (FIN) AF: 0.484 AC: 5121 AN: 10582

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30944 AN: 67958

Other (OTH) AF: 0.379 AC: 802 AN: 2116

Alfa AF: 0.413 Hom.: 67713

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Congenital sensory neuropathy with selective loss of small myelinated fibers (5)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.097
Sift	Uncertain	0.022	D
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.014
MPC		0.34
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.062
gMVP		0.57
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs6330; hg19: chr1-115829313; COSMIC: COSV65687373;