NM_002529.4:c.202C>T

Variant names:

• chr1-156861136-C-T
• rs779430325
• NM_002529.4:c.202C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_002529.4(NTRK1):​c.202C>T​(p.Leu68Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000492 in 1,423,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-156861136-C-T is Benign according to our data. Variant chr1-156861136-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1111320.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.

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.202C>T	p.Leu68Leu	synonymous	Exon 1 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.202C>T	p.Leu68Leu	synonymous	Exon 1 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.123-3218C>T		intron	N/A	NP_001007793.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.202C>T	p.Leu68Leu	synonymous	Exon 1 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.202C>T	p.Leu68Leu	synonymous	Exon 1 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.202C>T	p.Leu68Leu	synonymous	Exon 1 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180614 AF XY: 0.0000100

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000492 AC: 7 AN: 1423852 Hom.: 0 Cov.: 32 AF XY: 0.00000425 AC XY: 3 AN XY: 706122

African (AFR) AF: 0.00 AC: 0 AN: 33026

American (AMR) AF: 0.00 AC: 0 AN: 41654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25588

East Asian (EAS) AF: 0.00 AC: 0 AN: 38578

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5398

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1096802

Other (OTH) AF: 0.00 AC: 0 AN: 59064

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		1.2
PromoterAI		-0.021	Neutral
Mutation Taster		=100/0	polymorphism

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: rs779430325; hg19: chr1-156830928;