Genetic Variant NTRK1:p.Gly620Gly (chr1-156879176-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002529.4(NTRK1):c.1860C>T(p.Gly620Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 1,613,056 control chromosomes in the GnomAD database, including 480 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. G620G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 217 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 263 hom. )

Consequence

NTRK1
NM_002529.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -4.43

Publications

7 publications found

Variant links:

COSMIC-nc: COSV104662659

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

NTRK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 1-156879176-C-T is Benign according to our data. Variant chr1-156879176-C-T is described in ClinVar as Benign. ClinVar VariationId is 292893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NTRK1	NM_002529.4	MANE Select	c.1860C>T	p.Gly620Gly	synonymous	Exon 15 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.1842C>T	p.Gly614Gly	synonymous	Exon 14 of 16	NP_001012331.1	P04629-2
NTRK1	NM_001007792.1		c.1752C>T	p.Gly584Gly	synonymous	Exon 15 of 17	NP_001007793.1	P04629-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.1860C>T	p.Gly620Gly	synonymous	Exon 15 of 17	ENSP00000431418.1	P04629-1
NTRK1	ENST00000368196.7	TSL:1	c.1842C>T	p.Gly614Gly	synonymous	Exon 14 of 16	ENSP00000357179.3	P04629-2
NTRK1	ENST00000358660.3	TSL:2	c.1851C>T	p.Gly617Gly	synonymous	Exon 14 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4826

AN:

152074

Hom.:

217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00360

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0106

AC:

2632

AN:

248998

AF XY:

0.00857

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.00640

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.00396

Gnomad OTH exome

AF:

0.00557

GnomAD4 exome

AF:

0.00628

AC:

9173

AN:

1460864

Hom.:

263

Cov.:

AF XY:

0.00564

AC XY:

4101

AN XY:

726718

show subpopulations

African (AFR)

AF:

0.114

AC:

3804

AN:

33472

American (AMR)

AF:

0.00716

AC:

320

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00234

AC:

202

AN:

86202

European-Finnish (FIN)

AF:

0.000993

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00370

AC:

4107

AN:

1111164

Other (OTH)

AF:

0.0103

AC:

622

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

537

1073

1610

2146

2683

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0318

AC:

4834

AN:

152192

Hom.:

217

Cov.:

AF XY:

0.0301

AC XY:

2240

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.105

AC:

4367

AN:

41504

American (AMR)

AF:

0.00994

AC:

152

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00360

AC:

245

AN:

68018

Other (OTH)

AF:

0.0237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

228

456

683

911

1139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0296

Hom.:

129

Bravo

AF:

0.0363

EpiCase

AF:

0.00376

EpiControl

AF:

0.00409

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary insensitivity to pain with anhidrosis (7)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.96

(source)

DANN

Benign

0.71

PhyloP100

-4.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over