rs6336

Variant names:

• chr1-156879126-C-T
• rs6336
• NM_002529.4:c.1810C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-156879126-C-T
• chr1-156879126-C-A
• chr1-156879126-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002529.4(NTRK1):​c.1810C>T​(p.His604Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,612 control chromosomes in the GnomAD database, including 2,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H604H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (147 hom., cov: 31)
  • Exomes 𝑓: 0.055 (2511 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:17 O:1
• Conservation: PhyloP100: 7.83
• Publications: 56 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007919282).
• BP6: Variant 1-156879126-C-T is Benign according to our data. Variant chr1-156879126-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 37077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

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.1810C>T	p.His604Tyr	missense	Exon 15 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1792C>T	p.His598Tyr	missense	Exon 14 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.1702C>T	p.His568Tyr	missense	Exon 15 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.1810C>T	p.His604Tyr	missense	Exon 15 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.1792C>T	p.His598Tyr	missense	Exon 14 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.1801C>T	p.His601Tyr	missense	Exon 14 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5720 AN: 152056 Hom.: 147 Cov.: 31

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0687

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0564

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0572

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0416 AC: 10359 AN: 248732 AF XY: 0.0446

Gnomad AFR exome AF: 0.00851

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.0554

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0549 AC: 80241 AN: 1461438 Hom.: 2511 Cov.: 32 AF XY: 0.0553 AC XY: 40229 AN XY: 727022

African (AFR) AF: 0.00810 AC: 271 AN: 33474

American (AMR) AF: 0.0245 AC: 1094 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0647 AC: 1691 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39698

South Asian (SAS) AF: 0.0571 AC: 4921 AN: 86222

European-Finnish (FIN) AF: 0.0299 AC: 1598 AN: 53408

Middle Eastern (MID) AF: 0.0472 AC: 265 AN: 5610

European-Non Finnish (NFE) AF: 0.0604 AC: 67183 AN: 1111822

Other (OTH) AF: 0.0532 AC: 3209 AN: 60358

GnomAD4 genome AF: 0.0376 AC: 5717 AN: 152174 Hom.: 147 Cov.: 31 AF XY: 0.0351 AC XY: 2613 AN XY: 74394

African (AFR) AF: 0.0104 AC: 433 AN: 41512

American (AMR) AF: 0.0309 AC: 473 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0687 AC: 238 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0562 AC: 270 AN: 4802

European-Finnish (FIN) AF: 0.0263 AC: 279 AN: 10608

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0572 AC: 3890 AN: 67992

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0506 Hom.: 617

Bravo AF: 0.0366

TwinsUK AF: 0.0556 AC: 206

ALSPAC AF: 0.0584 AC: 225

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.0605 AC: 520

ExAC AF: 0.0422 AC: 5125

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0534

EpiControl AF: 0.0555

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Hereditary insensitivity to pain with anhidrosis (8)
-	-	6	not specified (6)
-	-	4	not provided (4)
1	-	-	Familial medullary thyroid carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0079	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.61
MPC		0.89
ClinPred		0.018	T
GERP RS		4.4
Varity_R		0.96
gMVP		0.68
Mutation Taster		=21/79	polymorphism (auto)

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: rs6336; hg19: chr1-156848918; COSMIC: COSV62324956;