Genetic Variant NM_001012338.3:c.*8023C>T (chr15-87868912-G-A) – 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.*8023C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 225,494 control chromosomes in the GnomAD database, including 49,206 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 0.65 ( 32175 hom., cov: 33)

Exomes 𝑓: 0.68 ( 17031 hom. )

Consequence

NTRK3
NM_001012338.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.346

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=-0.92).

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.*8023C>T		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.*8023C>T		3_prime_UTR_variant	Exon 20 of 20	1	NM_001012338.3	ENSP00000485864.1		Q16288-1
NTRK3	ENST00000394480.6 link	c.*8023C>T		3_prime_UTR_variant	Exon 19 of 19	5		ENSP00000377990.1		Q16288-3

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98550

AN:

152010

Hom.:

32150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.655

Gnomad AMR

AF:

0.650

Gnomad ASJ

AF:

0.685

Gnomad EAS

AF:

0.669

Gnomad SAS

AF:

0.574

Gnomad FIN

AF:

0.690

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.680

Gnomad OTH

AF:

0.660

GnomAD4 exome

AF:

0.680

AC:

49882

AN:

73368

Hom.:

17031

Cov.:

AF XY:

0.683

AC XY:

23207

AN XY:

33974

show subpopulations

African (AFR)

AF:

0.598

AC:

2098

AN:

3510

American (AMR)

AF:

0.629

AC:

1372

AN:

2180

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

3251

AN:

4726

East Asian (EAS)

AF:

0.731

AC:

7699

AN:

10536

South Asian (SAS)

AF:

0.596

AC:

384

AN:

644

European-Finnish (FIN)

AF:

0.672

AC:

AN:

Middle Eastern (MID)

AF:

0.621

AC:

278

AN:

448

European-Non Finnish (NFE)

AF:

0.680

AC:

30688

AN:

45132

Other (OTH)

AF:

0.664

AC:

4073

AN:

6134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

822

1643

2465

3286

4108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.648

AC:

98624

AN:

152126

Hom.:

32175

Cov.:

AF XY:

0.649

AC XY:

48238

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.588

AC:

24388

AN:

41504

American (AMR)

AF:

0.650

AC:

9941

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.685

AC:

2372

AN:

3464

East Asian (EAS)

AF:

0.668

AC:

3445

AN:

5156

South Asian (SAS)

AF:

0.572

AC:

2758

AN:

4820

European-Finnish (FIN)

AF:

0.690

AC:

7303

AN:

10578

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.680

AC:

46262

AN:

68000

Other (OTH)

AF:

0.656

AC:

1385

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1779

3557

5336

7114

8893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.643

Hom.:

3940

Bravo

AF:

0.646

Asia WGS

AF:

0.634

AC:

2208

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.55

(source)

DANN

Benign

0.60

PhyloP100

-0.35

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