NM_002529.4:c.212+10C>T

Variant names:

• chr1-156861156-C-T
• rs183517027
• NM_002529.4:c.212+10C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002529.4(NTRK1):​c.212+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,552,690 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: NTRK1 NM_002529.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.322
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-156861156-C-T is Benign according to our data. Variant chr1-156861156-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292872.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.212+10C>T		intron	N/A	NP_002520.2
	NTRK1	NM_001012331.2		c.212+10C>T		intron	N/A	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.123-3198C>T		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.212+10C>T		intron	N/A	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.212+10C>T		intron	N/A	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.212+10C>T		intron	N/A	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

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: 0.00156

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00114 AC: 170 AN: 149738 AF XY: 0.00104

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000116

Gnomad NFE exome AF: 0.00197

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00157 AC: 2203 AN: 1400376 Hom.: 3 Cov.: 32 AF XY: 0.00156 AC XY: 1077 AN XY: 692442

African (AFR) AF: 0.000216 AC: 7 AN: 32342

American (AMR) AF: 0.00223 AC: 85 AN: 38110

Ashkenazi Jewish (ASJ) AF: 0.0000789 AC: 2 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 37132

South Asian (SAS) AF: 0.0000497 AC: 4 AN: 80446

European-Finnish (FIN) AF: 0.0000772 AC: 3 AN: 38876

Middle Eastern (MID) AF: 0.000981 AC: 5 AN: 5096

European-Non Finnish (NFE) AF: 0.00186 AC: 2013 AN: 1084836

Other (OTH) AF: 0.00144 AC: 84 AN: 58204

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74486

African (AFR) AF: 0.000361 AC: 15 AN: 41562

American (AMR) AF: 0.00261 AC: 40 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00155

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Hereditary insensitivity to pain with anhidrosis (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.6
DANN	Benign	0.94
PhyloP100		-0.32
PromoterAI		-0.00060	Neutral
Mutation Taster		=100/0	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: rs183517027; hg19: chr1-156830948;