NM_002529.4:c.1738A>C

Variant names:

• chr1-156876505-A-C
• rs764541952
• NM_002529.4:c.1738A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002529.4(NTRK1):​c.1738A>C​(p.Thr580Pro) 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 pathogenic 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. T580S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.215
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

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.1738A>C	p.Thr580Pro	missense	Exon 14 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1720A>C	p.Thr574Pro	missense	Exon 13 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.1630A>C	p.Thr544Pro	missense	Exon 14 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.1738A>C	p.Thr580Pro	missense	Exon 14 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.1720A>C	p.Thr574Pro	missense	Exon 13 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.1729A>C	p.Thr577Pro	missense	Exon 13 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.21
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.64
Sift	Benign	0.086	T
Sift4G	Benign	0.099	T
Polyphen		0.94	P
Vest4		0.62
MutPred		0.80		Loss of catalytic residue at T580 (P = 0.1739)
MVP		0.96
MPC		0.98
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.82
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs764541952; hg19: chr1-156846297;