chr1-115286743-G-A

Variant names:

• chr1-115286743-G-A
• rs754287903
• NM_002506.3:c.53C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002506.3(NGF):​c.53C>T​(p.Ala18Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: NGF NM_002506.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.92
• Publications: 0 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGF	NM_002506.3	MANE Select	c.53C>T	p.Ala18Val	missense	Exon 3 of 3	NP_002497.2
	NGF	NM_001437545.1		c.53C>T	p.Ala18Val	missense	Exon 2 of 2	NP_001424474.1
	NGF-AS1	NR_157569.1		n.207+3503G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGF	ENST00000369512.3	TSL:1 MANE Select	c.53C>T	p.Ala18Val	missense	Exon 3 of 3	ENSP00000358525.2
	NGF	ENST00000675637.2		c.53C>T	p.Ala18Val	missense	Exon 2 of 2	ENSP00000502831.1
	NGF	ENST00000676038.2		c.53C>T	p.Ala18Val	missense	Exon 4 of 4	ENSP00000502380.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251478 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.0000454 AC XY: 33 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1112012

Other (OTH) AF: 0.000116 AC: 7 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.71		Loss of disorder (P = 0.0726)
MVP		0.75
MPC		1.1
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.84
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754287903; hg19: chr1-115829364; COSMIC: COSV65687683;