chr1-156876100-C-A

Variant names:

• chr1-156876100-C-A
• rs200575096
• NM_002529.4:c.1522C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_002529.4(NTRK1):​c.1522C>A​(p.Arg508Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.105
• Publications: 11 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 1-156876100-C-A is Benign according to our data. Variant chr1-156876100-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292887.
• BP7: Synonymous conserved (PhyloP=0.105 with no splicing effect.

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.1522C>A	p.Arg508Arg	synonymous	Exon 13 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1504C>A	p.Arg502Arg	synonymous	Exon 12 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.1414C>A	p.Arg472Arg	synonymous	Exon 13 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.1522C>A	p.Arg508Arg	synonymous	Exon 13 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.1504C>A	p.Arg502Arg	synonymous	Exon 12 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.1513C>A	p.Arg505Arg	synonymous	Exon 12 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251456 AF XY: 0.0000589

Gnomad AFR exome AF: 0.0000615

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: 0.000105

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000150 AC: 219 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.000131 AC XY: 95 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000192 AC: 214 AN: 1112012

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000152 Hom.: 1

Bravo AF: 0.0000453

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary insensitivity to pain with anhidrosis (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	NTRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200575096; hg19: chr1-156845892; COSMIC: COSV104662702;