1-156881473-C-A

Variant names:

• chr1-156881473-C-A
• rs145081333
• NM_002529.4:c.2222C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002529.4(NTRK1):​c.2222C>A​(p.Thr741Lys) variant causes a missense change. 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. T741M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.08
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

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.2222C>A	p.Thr741Lys	missense	Exon 17 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.2204C>A	p.Thr735Lys	missense	Exon 16 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.2114C>A	p.Thr705Lys	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.2222C>A	p.Thr741Lys	missense	Exon 17 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.2204C>A	p.Thr735Lys	missense	Exon 16 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.2213C>A	p.Thr738Lys	missense	Exon 16 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1423618 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 704760

African (AFR) AF: 0.00 AC: 0 AN: 32540

American (AMR) AF: 0.00 AC: 0 AN: 39162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 37380

South Asian (SAS) AF: 0.00 AC: 0 AN: 81122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092792

Other (OTH) AF: 0.00 AC: 0 AN: 58968

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.56	N
PhyloP100		6.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.68
Sift	Benign	0.067	T
Sift4G	Benign	0.65	T
Polyphen		0.75	P
Vest4		0.81
MutPred		0.55		Gain of ubiquitination at T741 (P = 0.0247)
MVP		0.92
MPC		0.98
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.81
Mutation Taster		=30/70	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: rs145081333; hg19: chr1-156851265;