NM_002529.4:c.641G>T

Variant names:

• chr1-156868571-G-T
• rs200132482
• NM_002529.4:c.641G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_002529.4(NTRK1):​c.641G>T​(p.Arg214Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,402,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.168
• Publications: 0 publications found

Genes affected

NTRK1 (HGNC:8031): (neurotrophic receptor tyrosine kinase 1) This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

NTRK1 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20162782).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002529.4. 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
	NTRK1	NM_002529.4	MANE Select	c.641G>T	p.Arg214Leu	missense	Exon 6 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.641G>T	p.Arg214Leu	missense	Exon 6 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.551G>T	p.Arg184Leu	missense	Exon 7 of 17	NP_001007793.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.641G>T	p.Arg214Leu	missense	Exon 6 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.641G>T	p.Arg214Leu	missense	Exon 6 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.641G>T	p.Arg214Leu	missense	Exon 6 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1402090 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 691830

African (AFR) AF: 0.00 AC: 0 AN: 31766

American (AMR) AF: 0.00 AC: 0 AN: 36152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36004

South Asian (SAS) AF: 0.00 AC: 0 AN: 79406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080540

Other (OTH) AF: 0.00 AC: 0 AN: 58124

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.22
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.17
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.042
Sift	Benign	0.62	T
Sift4G	Benign	0.64	T
Polyphen		0.083	B
Vest4		0.31
MutPred		0.52		Gain of catalytic residue at D210 (P = 0.2349)
MVP		0.72
MPC		0.32
ClinPred		0.079	T
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.61
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200132482; hg19: chr1-156838363;