rs138175552

Variant names:

• chr1-115286549-G-A
• rs138175552
• NM_002506.3:c.247C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002506.3(NGF):​c.247C>T​(p.Arg83Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,614,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: NGF NM_002506.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 7.52
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

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.247C>T	p.Arg83Cys	missense	Exon 3 of 3	NP_002497.2	P01138
	NGF	NM_001437545.1		c.247C>T	p.Arg83Cys	missense	Exon 2 of 2	NP_001424474.1
	NGF-AS1	NR_157569.1		n.207+3309G>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.247C>T	p.Arg83Cys	missense	Exon 3 of 3	ENSP00000358525.2	P01138
	NGF	ENST00000681124.1		c.-225C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000506364.1	A0A7P0TAZ6
	NGF	ENST00000675637.2		c.247C>T	p.Arg83Cys	missense	Exon 2 of 2	ENSP00000502831.1	P01138

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251214 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000366 AC: 535 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.000393 AC XY: 286 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000460 AC: 512 AN: 1112008

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000577 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	Congenital sensory neuropathy with selective loss of small myelinated fibers (5)
-	2	1	not provided (3)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.66
MVP		0.46
MPC		1.0
ClinPred		0.31	T
GERP RS		5.1
Varity_R		0.31
gMVP		0.44
Mutation Taster		=79/21	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: rs138175552; hg19: chr1-115829170; COSMIC: COSV65687867;