chr1-156879203-C-T

Variant names:

• chr1-156879203-C-T
• rs6337
• NM_002529.4:c.1887C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002529.4(NTRK1):​c.1887C>T​(p.Ala629Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,613,480 control chromosomes in the GnomAD database, including 369,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A629A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (25958 hom., cov: 31)
  • Exomes 𝑓: 0.67 (343382 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: -3.99
• Publications: 23 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 1-156879203-C-T is Benign according to our data. Variant chr1-156879203-C-T is described in ClinVar as Benign. ClinVar VariationId is 138564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.719 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	NM_002529.4	MANE Select	c.1887C>T	p.Ala629Ala	synonymous	Exon 15 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1869C>T	p.Ala623Ala	synonymous	Exon 14 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.1779C>T	p.Ala593Ala	synonymous	Exon 15 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.1887C>T	p.Ala629Ala	synonymous	Exon 15 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.1869C>T	p.Ala623Ala	synonymous	Exon 14 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.1878C>T	p.Ala626Ala	synonymous	Exon 14 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80948 AN: 151840 Hom.: 25959 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.578 AC: 143744 AN: 248724 AF XY: 0.582

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.575

Gnomad ASJ exome AF: 0.751

Gnomad EAS exome AF: 0.0396

Gnomad FIN exome AF: 0.732

Gnomad NFE exome AF: 0.724

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.667 AC: 975001 AN: 1461522 Hom.: 343382 Cov.: 70 AF XY: 0.661 AC XY: 480752 AN XY: 727024

African (AFR) AF: 0.193 AC: 6460 AN: 33480

American (AMR) AF: 0.578 AC: 25810 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 19605 AN: 26128

East Asian (EAS) AF: 0.0457 AC: 1814 AN: 39688

South Asian (SAS) AF: 0.398 AC: 34365 AN: 86246

European-Finnish (FIN) AF: 0.733 AC: 39134 AN: 53370

Middle Eastern (MID) AF: 0.603 AC: 3477 AN: 5766

European-Non Finnish (NFE) AF: 0.726 AC: 806890 AN: 1111816

Other (OTH) AF: 0.620 AC: 37446 AN: 60362

GnomAD4 genome AF: 0.533 AC: 80961 AN: 151958 Hom.: 25958 Cov.: 31 AF XY: 0.526 AC XY: 39055 AN XY: 74300

African (AFR) AF: 0.214 AC: 8866 AN: 41424

American (AMR) AF: 0.558 AC: 8530 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 2603 AN: 3470

East Asian (EAS) AF: 0.0506 AC: 261 AN: 5162

South Asian (SAS) AF: 0.371 AC: 1783 AN: 4808

European-Finnish (FIN) AF: 0.731 AC: 7724 AN: 10572

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.724 AC: 49181 AN: 67932

Other (OTH) AF: 0.554 AC: 1168 AN: 2110

Alfa AF: 0.661 Hom.: 48174

Bravo AF: 0.512

Asia WGS AF: 0.233 AC: 812 AN: 3478

EpiCase AF: 0.716

EpiControl AF: 0.717

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary insensitivity to pain with anhidrosis (5)
-	1	4	not specified (5)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	3.8
DANN	Benign	0.82
PhyloP100		-4.0
Mutation Taster		=98/2	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: rs6337; hg19: chr1-156848995; COSMIC: COSV62325231; COSMIC: COSV62325231;