Genetic Variant NTRK3:c.*742A>C (chr15-87876193-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001012338.3(NTRK3):c.*742A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 233,082 control chromosomes in the GnomAD database, including 49,248 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.64 ( 31626 hom., cov: 32)

Exomes 𝑓: 0.66 ( 17622 hom. )

Consequence

NTRK3
NM_001012338.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.81

Publications

9 publications found

Variant links:

Genes affected

NTRK3 (HGNC:8033): (neurotrophic receptor tyrosine kinase 3) This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

NTRK3 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NTRK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3 link	c.*742A>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000629765.3	NP_001012338.1	Q16288-1X5D2R1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3 link	c.*742A>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_001012338.3	ENSP00000485864.1		Q16288-1
NTRK3	ENST00000394480.6 link	c.*742A>C		3_prime_UTR_variant	Exon 19 of 19	5		ENSP00000377990.1		Q16288-3

Frequencies

GnomAD3 genomes

AF:

0.642

AC:

97529

AN:

151920

Hom.:

31594

Cov.:

show subpopulations

Gnomad AFR

AF:

0.622

Gnomad AMI

AF:

0.526

Gnomad AMR

AF:

0.561

Gnomad ASJ

AF:

0.683

Gnomad EAS

AF:

0.598

Gnomad SAS

AF:

0.469

Gnomad FIN

AF:

0.690

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.680

Gnomad OTH

AF:

0.637

GnomAD4 exome

AF:

0.657

AC:

53286

AN:

81044

Hom.:

17622

Cov.:

AF XY:

0.660

AC XY:

24631

AN XY:

37318

show subpopulations

African (AFR)

AF:

0.638

AC:

2465

AN:

3864

American (AMR)

AF:

0.524

AC:

1300

AN:

2480

Ashkenazi Jewish (ASJ)

AF:

0.680

AC:

3462

AN:

5092

East Asian (EAS)

AF:

0.633

AC:

7252

AN:

11458

South Asian (SAS)

AF:

0.481

AC:

338

AN:

702

European-Finnish (FIN)

AF:

0.659

AC:

120

AN:

182

Middle Eastern (MID)

AF:

0.549

AC:

268

AN:

488

European-Non Finnish (NFE)

AF:

0.673

AC:

33656

AN:

50028

Other (OTH)

AF:

0.656

AC:

4425

AN:

6750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

931

1862

2794

3725

4656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.642

AC:

97611

AN:

152038

Hom.:

31626

Cov.:

AF XY:

0.638

AC XY:

47399

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.622

AC:

25822

AN:

41486

American (AMR)

AF:

0.561

AC:

8573

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

2370

AN:

3470

East Asian (EAS)

AF:

0.598

AC:

3080

AN:

5154

South Asian (SAS)

AF:

0.468

AC:

2254

AN:

4818

European-Finnish (FIN)

AF:

0.690

AC:

7290

AN:

10572

Middle Eastern (MID)

AF:

0.565

AC:

165

AN:

292

European-Non Finnish (NFE)

AF:

0.680

AC:

46240

AN:

67954

Other (OTH)

AF:

0.634

AC:

1338

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1813

3625

5438

7250

9063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.658

Hom.:

100680

Bravo

AF:

0.634

Asia WGS

AF:

0.555

AC:

1932

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.017

(source)

DANN

Benign

0.40

PhyloP100

-2.8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over