rs144901788

Variant names:

• chr1-156875639-G-A
• rs144901788
• NM_002529.4:c.1474G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156875639-G-A
• chr1-156875639-G-T

Variant summary

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

The NM_002529.4(NTRK1):​c.1474G>A​(p.Glu492Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00069 in 1,613,264 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 6.64
• Publications: 18 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: Uncertain_significance. The variant received 0 ACMG points.

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.1474G>A	p.Glu492Lys	missense	Exon 12 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1456G>A	p.Glu486Lys	missense	Exon 11 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.1366G>A	p.Glu456Lys	missense	Exon 12 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.1474G>A	p.Glu492Lys	missense	Exon 12 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.1456G>A	p.Glu486Lys	missense	Exon 11 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.1456G>A	p.Glu486Lys	missense	Exon 11 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.000376 AC: 57 AN: 151796 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000454 AC: 114 AN: 250934 AF XY: 0.000361

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000723 AC: 1056 AN: 1461468 Hom.: 1 Cov.: 35 AF XY: 0.000696 AC XY: 506 AN XY: 727070

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44718

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.000170 AC: 9 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000902 AC: 1003 AN: 1111984

Other (OTH) AF: 0.000530 AC: 32 AN: 60390

GnomAD4 genome AF: 0.000376 AC: 57 AN: 151796 Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 24 AN XY: 74098

African (AFR) AF: 0.000194 AC: 8 AN: 41316

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000628 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Hereditary insensitivity to pain with anhidrosis (4)
-	3	-	not provided (3)
-	1	-	Charcot-Marie-Tooth disease (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.030	D
Polyphen		0.069	B
Vest4		0.85
MVP		0.96
MPC		0.36
ClinPred		0.075	T
GERP RS		4.7
Varity_R		0.84
gMVP		0.73
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs144901788; hg19: chr1-156845431; COSMIC: COSV62324977; COSMIC: COSV62324977;