NM_002529.4:c.865C>G

Variant names:

• chr1-156873647-C-G
• rs137979116
• NM_002529.4:c.865C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002529.4(NTRK1):​c.865C>G​(p.Gln289Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Q289H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06857085).

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.865C>G	p.Gln289Glu	missense	Exon 8 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.865C>G	p.Gln289Glu	missense	Exon 8 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.775C>G	p.Gln259Glu	missense	Exon 9 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.865C>G	p.Gln289Glu	missense	Exon 8 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.865C>G	p.Gln289Glu	missense	Exon 8 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.865C>G	p.Gln289Glu	missense	Exon 8 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.1
DANN	Benign	0.85
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.50
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.078
Sift	Benign	0.35	T
Sift4G	Benign	0.38	T
Polyphen		0.012	B
Vest4		0.15
MutPred		0.54		Gain of loop (P = 0.1069)
MVP		0.67
MPC		0.26
ClinPred		0.065	T
GERP RS		3.0
Varity_R		0.14
gMVP		0.64
Mutation Taster		=96/4	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: rs137979116; hg19: chr1-156843439;