1-156873722-C-T

Variant names:

• chr1-156873722-C-T
• rs137994522
• NM_002529.4:c.940C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_002529.4(NTRK1):​c.940C>T​(p.Arg314Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,612,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.38
• Publications: 12 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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 (MetaRNN=0.013421059).
• BP6: Variant 1-156873722-C-T is Benign according to our data. Variant chr1-156873722-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245994.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	NM_002529.4	MANE Select	c.940C>T	p.Arg314Cys	missense	Exon 8 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.940C>T	p.Arg314Cys	missense	Exon 8 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.850C>T	p.Arg284Cys	missense	Exon 9 of 17	NP_001007793.1	P04629-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.940C>T	p.Arg314Cys	missense	Exon 8 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.940C>T	p.Arg314Cys	missense	Exon 8 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.940C>T	p.Arg314Cys	missense	Exon 8 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152166 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000271 AC: 67 AN: 247302 AF XY: 0.000261

Gnomad AFR exome AF: 0.00318

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1460382 Hom.: 1 Cov.: 32 AF XY: 0.000127 AC XY: 92 AN XY: 726386

African (AFR) AF: 0.00386 AC: 129 AN: 33440

American (AMR) AF: 0.0000672 AC: 3 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000291 AC: 25 AN: 85960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5532

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111574

Other (OTH) AF: 0.000299 AC: 18 AN: 60300

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152284 Hom.: 1 Cov.: 31 AF XY: 0.00114 AC XY: 85 AN XY: 74462

African (AFR) AF: 0.00407 AC: 169 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Hereditary cancer (1)
-	-	1	Hereditary insensitivity to pain with anhidrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.19
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.59
MPC		0.91
ClinPred		0.063	T
GERP RS		5.2
Varity_R		0.24
gMVP		0.89
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: rs137994522; hg19: chr1-156843514; COSMIC: COSV62326926; COSMIC: COSV62326926;