Genetic Variant NM_001012338.3:c.573C>T (chr15-88137453-G-A) – 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_001012338.3(NTRK3):c.573C>T(p.Asn191Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,770 control chromosomes in the GnomAD database, including 59,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6598 hom., cov: 33)

Exomes 𝑓: 0.27 ( 52988 hom. )

Consequence

NTRK3
NM_001012338.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.570

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 15-88137453-G-A is Benign according to our data. Variant chr15-88137453-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.57 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3 link	c.573C>T	p.Asn191Asn	synonymous_variant	Exon 7 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.573C>T	p.Asn191Asn	synonymous_variant	Exon 7 of 20	1	NM_001012338.3	ENSP00000485864.1		Q16288-1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43764

AN:

152022

Hom.:

6584

Cov.:

show subpopulations

Gnomad AFR

AF:

0.372

Gnomad AMI

AF:

0.276

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.333

Gnomad EAS

AF:

0.228

Gnomad SAS

AF:

0.265

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.281

GnomAD2 exomes

AF:

0.257

AC:

64465

AN:

251146

AF XY:

0.257

show subpopulations

Gnomad AFR exome

AF:

0.377

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.343

Gnomad EAS exome

AF:

0.228

Gnomad FIN exome

AF:

0.243

Gnomad NFE exome

AF:

0.268

Gnomad OTH exome

AF:

0.259

GnomAD4 exome

AF:

0.267

AC:

389969

AN:

1461630

Hom.:

52988

Cov.:

AF XY:

0.267

AC XY:

194245

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.383

AC:

12836

AN:

33472

American (AMR)

AF:

0.155

AC:

6911

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

8958

AN:

26134

East Asian (EAS)

AF:

0.202

AC:

8002

AN:

39700

South Asian (SAS)

AF:

0.268

AC:

23144

AN:

86242

European-Finnish (FIN)

AF:

0.247

AC:

13160

AN:

53368

Middle Eastern (MID)

AF:

0.324

AC:

1855

AN:

5726

European-Non Finnish (NFE)

AF:

0.268

AC:

298287

AN:

1111882

Other (OTH)

AF:

0.278

AC:

16816

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

16941

33882

50824

67765

84706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10086

20172

30258

40344

50430

<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:

0.288

AC:

43819

AN:

152140

Hom.:

6598

Cov.:

AF XY:

0.285

AC XY:

21191

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.372

AC:

15446

AN:

41500

American (AMR)

AF:

0.197

AC:

3013

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

1156

AN:

3472

East Asian (EAS)

AF:

0.228

AC:

1178

AN:

5160

South Asian (SAS)

AF:

0.266

AC:

1280

AN:

4818

European-Finnish (FIN)

AF:

0.239

AC:

2527

AN:

10594

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.269

AC:

18302

AN:

67974

Other (OTH)

AF:

0.284

AC:

601

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1606

3212

4819

6425

8031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.285

Hom.:

4050

Bravo

AF:

0.289

Asia WGS

AF:

0.259

AC:

902

AN:

3478

EpiCase

AF:

0.271

EpiControl

AF:

0.262

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.9

(source)

DANN

Benign

0.63

PhyloP100

-0.57

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over