chr1-156873858-A-G

Variant names:

• chr1-156873858-A-G
• rs121964869
• NM_002529.4:c.1076A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002529.4(NTRK1):​c.1076A>G​(p.Tyr359Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y359Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 9.22
• Publications: 6 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 1-156873858-A-G is Pathogenic according to our data. Variant chr1-156873858-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12311.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	NM_002529.4	MANE Select	c.1076A>G	p.Tyr359Cys	missense	Exon 8 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1076A>G	p.Tyr359Cys	missense	Exon 8 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.986A>G	p.Tyr329Cys	missense	Exon 9 of 17	NP_001007793.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.1076A>G	p.Tyr359Cys	missense	Exon 8 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.1076A>G	p.Tyr359Cys	missense	Exon 8 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.1076A>G	p.Tyr359Cys	missense	Exon 8 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454308 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722762

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 43910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.00 AC: 0 AN: 84966

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108374

Other (OTH) AF: 0.00 AC: 0 AN: 60048

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease (1)
1	-	-	Hereditary insensitivity to pain with anhidrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.060	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.72		Loss of loop (P = 0.1242)
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs121964869; hg19: chr1-156843650;