1-156864735-G-C

Position:

• chr1-156864735-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_002529.4(NTRK1):​c.295G>C​(p.Val99Leu) 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. 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. V99M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a repeat LRR 1 (size 23) in uniprot entity NTRK1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3166191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.295G>C	p.Val99Leu	missense_variant	3/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.295G>C	p.Val99Leu	missense_variant	3/16		NP_001012331.1
NTRK1	NM_001007792.1	c.205G>C	p.Val69Leu	missense_variant	4/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.295G>C	p.Val99Leu	missense_variant	3/17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;.;T;T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.1	.;M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.87	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.11, 0.33	.;B;B;.
Vest4		0.52
MutPred		0.29		.;Loss of MoRF binding (P = 0.1424);Loss of MoRF binding (P = 0.1424);Loss of MoRF binding (P = 0.1424);
MVP		0.94
MPC		0.35
ClinPred		0.38	T
GERP RS		4.2
Varity_R		0.54
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156834527;