rs80356674

Variant names:

• chr1-156873600-T-A
• rs80356674
• NM_002529.4:c.851-33T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156873600-T-A
• chr1-156873600-T-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_002529.4(NTRK1):​c.851-33T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,443,816 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001378075: Studies have shown that this variant results in retention of 137 nucleotides from intron 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID:10982191)." and additional evidence is available in ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NTRK1 NM_002529.4 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: -0.559
• Publications: 28 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001378075: Studies have shown that this variant results in retention of 137 nucleotides from intron 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10982191).; SCV002765816: Published functional studies demonstrate a damaging effect (activation of upstream cryptic splice acceptor site resulting in aberrant splicing in vitro and incorporation of an abberant fragment into the mRNA) (Miura et al., 2000); PMID: 23112235, 30774415, 34674383, 34938316, 25356970, 28345382, 19618435, 27265460, 29770739, 30201336, 29619836, 31857517, 32219930, 30677517, 33422294, 33748046, 32901917, 10982191
• PP5: Variant 1-156873600-T-A is Pathogenic according to our data. Variant chr1-156873600-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 21308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.851-33T>A		intron	N/A	NP_002520.2
	NTRK1	NM_001012331.2		c.851-33T>A		intron	N/A	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.761-33T>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.851-33T>A		intron	N/A	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.851-33T>A		intron	N/A	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.851-33T>A		intron	N/A	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000340 AC: 8 AN: 235406 AF XY: 0.0000232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000446

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1443816 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 10 AN XY: 718650

African (AFR) AF: 0.00 AC: 0 AN: 33160

American (AMR) AF: 0.00 AC: 0 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.000455 AC: 18 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 84648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101884

Other (OTH) AF: 0.00 AC: 0 AN: 59686

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Hereditary insensitivity to pain with anhidrosis (7)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.0
DANN	Benign	0.85
PhyloP100		-0.56
BranchPoint Hunter		6.0
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs80356674; hg19: chr1-156843392;