15-87885845-A-G

Variant names:

• chr15-87885845-A-G
• rs11633200
• NM_001012338.3:c.2134-110T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001012338.3(NTRK3):​c.2134-110T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 417,606 control chromosomes in the GnomAD database, including 72,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (22393 hom., cov: 31)
  • Exomes 𝑓: 0.60 (49742 hom.)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.642
• Publications: 2 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 15-87885845-A-G is Benign according to our data. Variant chr15-87885845-A-G is described in ClinVar as Benign. ClinVar VariationId is 1223297.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.2134-110T>C		intron_variant	Intron 17 of 19	ENST00000629765.3	NP_001012338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3	c.2134-110T>C		intron_variant	Intron 17 of 19	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79531 AN: 151594 Hom.: 22387 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.540

GnomAD4 exome AF: 0.605 AC: 160751 AN: 265894 Hom.: 49742 AF XY: 0.604 AC XY: 81682 AN XY: 135290

African (AFR) AF: 0.284 AC: 2107 AN: 7412

American (AMR) AF: 0.576 AC: 4077 AN: 7076

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 5712 AN: 9168

East Asian (EAS) AF: 0.646 AC: 14584 AN: 22570

South Asian (SAS) AF: 0.411 AC: 3143 AN: 7640

European-Finnish (FIN) AF: 0.608 AC: 12633 AN: 20774

Middle Eastern (MID) AF: 0.478 AC: 632 AN: 1322

European-Non Finnish (NFE) AF: 0.624 AC: 107996 AN: 173006

Other (OTH) AF: 0.583 AC: 9867 AN: 16926

GnomAD4 genome AF: 0.524 AC: 79548 AN: 151712 Hom.: 22393 Cov.: 31 AF XY: 0.524 AC XY: 38848 AN XY: 74148

African (AFR) AF: 0.298 AC: 12353 AN: 41442

American (AMR) AF: 0.576 AC: 8757 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2190 AN: 3460

East Asian (EAS) AF: 0.607 AC: 3136 AN: 5164

South Asian (SAS) AF: 0.452 AC: 2181 AN: 4824

European-Finnish (FIN) AF: 0.606 AC: 6393 AN: 10544

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42835 AN: 67758

Other (OTH) AF: 0.539 AC: 1133 AN: 2102

Alfa AF: 0.407 Hom.: 1542

Bravo AF: 0.516

Asia WGS AF: 0.499 AC: 1733 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

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	-0.36
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11633200; hg19: chr15-88429076;