rs200815412

Variant names:

• chr1-156861091-G-A
• rs200815412
• NM_002529.4:c.157G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156861091-G-A
• chr1-156861091-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002529.4(NTRK1):​c.157G>A​(p.Asp53Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,431,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D53H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.245
• Publications: 5 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07954708).

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.157G>A	p.Asp53Asn	missense	Exon 1 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.157G>A	p.Asp53Asn	missense	Exon 1 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.123-3263G>A		intron	N/A	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.157G>A	p.Asp53Asn	missense	Exon 1 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.157G>A	p.Asp53Asn	missense	Exon 1 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.157G>A	p.Asp53Asn	missense	Exon 1 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000508 AC: 1 AN: 196792 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000489 AC: 7 AN: 1431902 Hom.: 0 Cov.: 32 AF XY: 0.00000563 AC XY: 4 AN XY: 710846

African (AFR) AF: 0.00 AC: 0 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 42810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 38872

South Asian (SAS) AF: 0.00 AC: 0 AN: 83128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00000636 AC: 7 AN: 1101374

Other (OTH) AF: 0.00 AC: 0 AN: 59344

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary insensitivity to pain with anhidrosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.24
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.20
Sift	Benign	0.40	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.42		Loss of catalytic residue at D53 (P = 0.0292)
MVP		0.76
MPC		0.24
ClinPred		0.052	T
GERP RS		0.76
PromoterAI		0.098	Neutral
Varity_R		0.19
gMVP		0.23
Mutation Taster		=93/7	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: rs200815412; hg19: chr1-156830883;