rs11466110

Variant names:

• chr1-115286582-C-T
• rs11466110
• NM_002506.3:c.214G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002506.3(NGF):​c.214G>A​(p.Val72Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,204 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V72V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0067 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (16 hom.)
• Consequence: NGF NM_002506.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.61
• Publications: 9 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=0.008228123).
• BP6: Variant 1-115286582-C-T is Benign according to our data. Variant chr1-115286582-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00673 (1025/152328) while in subpopulation AFR AF = 0.0237 (985/41578). AF 95% confidence interval is 0.0225. There are 4 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.214G>A	p.Val72Met	missense	Exon 3 of 3	NP_002497.2
	NGF	NM_001437545.1		c.214G>A	p.Val72Met	missense	Exon 2 of 2	NP_001424474.1
	NGF-AS1	NR_157569.1		n.207+3342C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGF	ENST00000369512.3	TSL:1 MANE Select	c.214G>A	p.Val72Met	missense	Exon 3 of 3	ENSP00000358525.2
	NGF	ENST00000681124.1		c.-258G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000506364.1
	NGF	ENST00000675637.2		c.214G>A	p.Val72Met	missense	Exon 2 of 2	ENSP00000502831.1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1023 AN: 152210 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00153 AC: 384 AN: 251166 AF XY: 0.00100

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000678 AC: 991 AN: 1461876 Hom.: 16 Cov.: 30 AF XY: 0.000562 AC XY: 409 AN XY: 727240

African (AFR) AF: 0.0222 AC: 742 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44724

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

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000620 AC: 69 AN: 1112008

Other (OTH) AF: 0.00180 AC: 109 AN: 60396

GnomAD4 genome AF: 0.00673 AC: 1025 AN: 152328 Hom.: 4 Cov.: 32 AF XY: 0.00650 AC XY: 484 AN XY: 74470

African (AFR) AF: 0.0237 AC: 985 AN: 41578

American (AMR) AF: 0.00150 AC: 23 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68036

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00274 Hom.: 9

Bravo AF: 0.00765

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.38	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.23
MVP		0.68
MPC		1.1
ClinPred		0.013	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.57
Mutation Taster		=90/10	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: rs11466110; hg19: chr1-115829203;