rs145823996

Variant names:

• chr1-156873850-C-A
• rs145823996
• NM_002529.4:c.1068C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156873850-C-A
• chr1-156873850-C-G
• chr1-156873850-C-T

Variant summary

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

The NM_002529.4(NTRK1):​c.1068C>A​(p.Asn356Lys) 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. Synonymous variant affecting the same amino acid position (i.e. N356N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.998
• Publications: 1 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, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.1068C>A	p.Asn356Lys	missense_variant	Exon 8 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.1068C>A	p.Asn356Lys	missense_variant	Exon 8 of 16		NP_001012331.1
NTRK1	NM_001007792.1	c.978C>A	p.Asn326Lys	missense_variant	Exon 9 of 17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.1068C>A	p.Asn356Lys	missense_variant	Exon 8 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;.;D;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.9	.;M;M;.
PhyloP100		-1.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.4	D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.82
MutPred		0.51		.;Gain of ubiquitination at N356 (P = 0.0388);Gain of ubiquitination at N356 (P = 0.0388);Gain of ubiquitination at N356 (P = 0.0388);
MVP		0.74
MPC		0.95
ClinPred		1.0	D
GERP RS		-1.8
Varity_R		0.83
gMVP		0.98
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145823996; hg19: chr1-156843642;