NM_002529.4:c.287+49G>T

Variant names:

• chr1-156864477-G-T
• rs1800878
• NM_002529.4:c.287+49G>T

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.287+49G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,583,284 control chromosomes in the GnomAD database, including 850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (110 hom., cov: 32)
  • Exomes 𝑓: 0.028 (740 hom.)
• Consequence: NTRK1 NM_002529.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.169
• Publications: 7 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.82).
• BP6: Variant 1-156864477-G-T is Benign according to our data. Variant chr1-156864477-G-T is described in ClinVar as Benign. ClinVar VariationId is 1266752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0811 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	NM_002529.4	MANE Select	c.287+49G>T		intron	N/A	NP_002520.2
	NTRK1	NM_001012331.2		c.287+49G>T		intron	N/A	NP_001012331.1
	NTRK1	NM_001007792.1		c.197+49G>T		intron	N/A	NP_001007793.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.287+49G>T		intron	N/A	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.287+49G>T		intron	N/A	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.287+49G>T		intron	N/A	ENSP00000351486.3

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4821 AN: 152084 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0279

GnomAD2 exomes AF: 0.0291 AC: 7162 AN: 245920 AF XY: 0.0284

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.00956

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.0941

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0284 AC: 40683 AN: 1431082 Hom.: 740 Cov.: 25 AF XY: 0.0281 AC XY: 20050 AN XY: 713832

African (AFR) AF: 0.0426 AC: 1398 AN: 32850

American (AMR) AF: 0.0106 AC: 472 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 478 AN: 25904

East Asian (EAS) AF: 0.0913 AC: 3607 AN: 39506

South Asian (SAS) AF: 0.0250 AC: 2137 AN: 85516

European-Finnish (FIN) AF: 0.0194 AC: 1034 AN: 53234

Middle Eastern (MID) AF: 0.0129 AC: 73 AN: 5678

European-Non Finnish (NFE) AF: 0.0275 AC: 29813 AN: 1084552

Other (OTH) AF: 0.0281 AC: 1671 AN: 59362

GnomAD4 genome AF: 0.0317 AC: 4823 AN: 152202 Hom.: 110 Cov.: 32 AF XY: 0.0313 AC XY: 2332 AN XY: 74398

African (AFR) AF: 0.0422 AC: 1752 AN: 41514

American (AMR) AF: 0.0163 AC: 250 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.0877 AC: 453 AN: 5164

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4822

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1927 AN: 68006

Other (OTH) AF: 0.0271 AC: 57 AN: 2102

Alfa AF: 0.0281 Hom.: 180

Bravo AF: 0.0322

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.89
PhyloP100		0.17
Mutation Taster		=100/0	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: rs1800878; hg19: chr1-156834269;