1-156860950-C-G

Variant names:

• chr1-156860950-C-G
• rs201472270
• NM_002529.4:c.16C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002529.4(NTRK1):​c.16C>G​(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,343,162 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict 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. R6W) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.668
• 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 2 ACMG points.

• 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.16C>G	p.Arg6Gly	missense	Exon 1 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.16C>G	p.Arg6Gly	missense	Exon 1 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.123-3404C>G		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.16C>G	p.Arg6Gly	missense	Exon 1 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.16C>G	p.Arg6Gly	missense	Exon 1 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.16C>G	p.Arg6Gly	missense	Exon 1 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1343162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 661606

African (AFR) AF: 0.0000367 AC: 1 AN: 27272

American (AMR) AF: 0.00 AC: 0 AN: 30480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23508

East Asian (EAS) AF: 0.00 AC: 0 AN: 31612

South Asian (SAS) AF: 0.00 AC: 0 AN: 74144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3944

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062878

Other (OTH) AF: 0.00 AC: 0 AN: 55972

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.0091	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.67
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.28
Sift	Benign	0.040	D
Sift4G	Uncertain	0.055	T
Polyphen		0.76	P
Vest4		0.45
MutPred		0.29		Loss of methylation at R6 (P = 0.0232)
MVP		0.91
MPC		0.35
ClinPred		0.60	D
GERP RS		4.2
PromoterAI		-0.037	Neutral
Varity_R		0.19
gMVP		0.50
Mutation Taster		=94/6	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: rs201472270; hg19: chr1-156830742;