dbSNP rs1007211: NTRK1:p.Gly18Glu (chr1-156860987-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002529.4(NTRK1):c.53G>A(p.Gly18Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,527,666 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. G18G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0091 ( 11 hom., cov: 33)

Exomes 𝑓: 0.013 ( 152 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.222

Publications

20 publications found

Variant links:

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

NTRK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071440935).

BP6

Variant 1-156860987-G-A is Benign according to our data. Variant chr1-156860987-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0134 (18393/1375370) while in subpopulation NFE AF = 0.016 (17258/1076308). AF 95% confidence interval is 0.0158. There are 152 homozygotes in GnomAdExome4. There are 8726 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NTRK1	NM_002529.4	MANE Select	c.53G>A	p.Gly18Glu	missense	Exon 1 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.53G>A	p.Gly18Glu	missense	Exon 1 of 16	NP_001012331.1
NTRK1	NM_001007792.1		c.123-3367G>A		intron	N/A	NP_001007793.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.53G>A	p.Gly18Glu	missense	Exon 1 of 17	ENSP00000431418.1
NTRK1	ENST00000368196.7	TSL:1	c.53G>A	p.Gly18Glu	missense	Exon 1 of 16	ENSP00000357179.3
NTRK1	ENST00000358660.3	TSL:2	c.53G>A	p.Gly18Glu	missense	Exon 1 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes

AF:

0.00909

AC:

1384

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00621

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00745

AC:

911

AN:

122212

AF XY:

0.00760

show subpopulations

Gnomad AFR exome

AF:

0.00227

Gnomad AMR exome

AF:

0.00323

Gnomad ASJ exome

AF:

0.00311

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00895

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.0134

AC:

18393

AN:

1375370

Hom.:

152

Cov.:

AF XY:

0.0129

AC XY:

8726

AN XY:

678774

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

30014

American (AMR)

AF:

0.00427

AC:

151

AN:

35390

Ashkenazi Jewish (ASJ)

AF:

0.00399

AC:

AN:

24808

East Asian (EAS)

AF:

0.0000287

AC:

AN:

34822

South Asian (SAS)

AF:

0.000308

AC:

AN:

77972

European-Finnish (FIN)

AF:

0.00828

AC:

285

AN:

34424

Middle Eastern (MID)

AF:

0.00360

AC:

AN:

4170

European-Non Finnish (NFE)

AF:

0.0160

AC:

17258

AN:

1076308

Other (OTH)

AF:

0.00879

AC:

505

AN:

57462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1147

2294

3442

4589

5736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

654

1308

1962

2616

3270

<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:

0.00908

AC:

1383

AN:

152296

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

612

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41568

American (AMR)

AF:

0.00653

AC:

100

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00621

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0156

AC:

1059

AN:

68012

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0109

Hom.:

Bravo

AF:

0.00865

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00274

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00319

AC:

295

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary insensitivity to pain with anhidrosis (5)

not specified (5)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

PhyloP100

0.22

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.99

REVEL

Benign

0.13

Sift

Benign

0.11

Sift4G

Benign

0.080

Polyphen

0.97

Vest4

0.53

MVP

0.87

MPC

0.34

ClinPred

0.0045

GERP RS

2.7

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.39

Mutation Taster

=100/0

polymorphism

(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