rs2274498

Variant names:

• chr1-156873862-G-A
• rs2274498
• NM_002529.4:c.1080G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156873862-G-A
• chr1-156873862-G-C
• chr1-156873862-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002529.4(NTRK1):​c.1080G>A​(p.Thr360Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,603,020 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T360T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.81
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-156873862-G-A is Benign according to our data. Variant chr1-156873862-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00139 (212/152244) while in subpopulation EAS AF = 0.0357 (185/5182). AF 95% confidence interval is 0.0315. There are 6 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR 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.1080G>A	p.Thr360Thr	synonymous	Exon 8 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1080G>A	p.Thr360Thr	synonymous	Exon 8 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.990G>A	p.Thr330Thr	synonymous	Exon 9 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.1080G>A	p.Thr360Thr	synonymous	Exon 8 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.1080G>A	p.Thr360Thr	synonymous	Exon 8 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000956587.1		c.947G>A	p.Arg316His	missense	Exon 7 of 13	ENSP00000626646.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152126 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.00319 AC: 731 AN: 228972 AF XY: 0.00301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0372

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000686

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00109 AC: 1585 AN: 1450776 Hom.: 32 Cov.: 32 AF XY: 0.00113 AC XY: 811 AN XY: 720746

African (AFR) AF: 0.0000301 AC: 1 AN: 33178

American (AMR) AF: 0.0000460 AC: 2 AN: 43460

Ashkenazi Jewish (ASJ) AF: 0.00108 AC: 28 AN: 25808

East Asian (EAS) AF: 0.0317 AC: 1238 AN: 39104

South Asian (SAS) AF: 0.00170 AC: 144 AN: 84500

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52500

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5748

European-Non Finnish (NFE) AF: 0.0000840 AC: 93 AN: 1106580

Other (OTH) AF: 0.00125 AC: 75 AN: 59898

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152244 Hom.: 6 Cov.: 31 AF XY: 0.00165 AC XY: 123 AN XY: 74438

African (AFR) AF: 0.0000482 AC: 2 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.0357 AC: 185 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

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: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.00183

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.5
DANN	Benign	0.90
PhyloP100		-3.8
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: rs2274498; hg19: chr1-156843654; COSMIC: COSV62327218; COSMIC: COSV62327218;