rs367836863

Variant names:

• chr1-156868180-G-A
• rs367836863
• NM_002529.4:c.505G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156868180-G-A
• chr1-156868180-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002529.4(NTRK1):​c.505G>A​(p.Gly169Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,613,722 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. G169G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0900
• Publications: 16 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058012307).
• BP6: Variant 1-156868180-G-A is Benign according to our data. Variant chr1-156868180-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 246246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.505G>A	p.Gly169Arg	missense	Exon 5 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.505G>A	p.Gly169Arg	missense	Exon 5 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.415G>A	p.Gly139Arg	missense	Exon 6 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.505G>A	p.Gly169Arg	missense	Exon 5 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.505G>A	p.Gly169Arg	missense	Exon 5 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.505G>A	p.Gly169Arg	missense	Exon 5 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152256 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00413

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000813 AC: 204 AN: 250826 AF XY: 0.000973

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00109

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000523 AC: 765 AN: 1461348 Hom.: 2 Cov.: 34 AF XY: 0.000666 AC XY: 484 AN XY: 726996

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00444 AC: 383 AN: 86258

European-Finnish (FIN) AF: 0.000870 AC: 46 AN: 52880

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000254 AC: 282 AN: 1112010

Other (OTH) AF: 0.000530 AC: 32 AN: 60394

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152374 Hom.: 2 Cov.: 33 AF XY: 0.000617 AC XY: 46 AN XY: 74518

African (AFR) AF: 0.0000481 AC: 2 AN: 41588

American (AMR) AF: 0.000196 AC: 3 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4834

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000407 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000807 AC: 98

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary insensitivity to pain with anhidrosis (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.86	L
PhyloP100		0.090
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.075
Sift	Benign	0.27	T
Sift4G	Benign	0.14	T
Polyphen		0.046	B
Vest4		0.25
MutPred		0.22		Loss of catalytic residue at V170 (P = 0.0334)
MVP		0.91
MPC		0.30
ClinPred		0.0097	T
GERP RS		1.4
Varity_R		0.12
gMVP		0.46
Mutation Taster		=96/4	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: rs367836863; hg19: chr1-156837972; COSMIC: COSV62328528; COSMIC: COSV62328528;