1-156881548-G-T

Variant names:

• chr1-156881548-G-T
• rs764581997
• NM_002529.4:c.2297G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002529.4(NTRK1):​c.2297G>T​(p.Arg766Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R766W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 3 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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage

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.2297G>T	p.Arg766Leu	missense	Exon 17 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.2279G>T	p.Arg760Leu	missense	Exon 16 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.2189G>T	p.Arg730Leu	missense	Exon 17 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.2297G>T	p.Arg766Leu	missense	Exon 17 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.2279G>T	p.Arg760Leu	missense	Exon 16 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.2288G>T	p.Arg763Leu	missense	Exon 16 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 237846 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000935

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.72	N
PhyloP100		10
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.023	D
Polyphen		0.076	B
Vest4		0.71
MutPred		0.51		Loss of disorder (P = 0.0341)
MVP		0.95
MPC		0.80
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.70
gMVP		0.76
Mutation Taster		=12/88	disease causing

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: rs764581997; hg19: chr1-156851340; COSMIC: COSV62323137;