rs4887380

Variant names:

• chr15-88184520-A-T
• rs4887380
• NM_001012338.3:c.249-221T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001012338.3(NTRK3):​c.249-221T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,112 control chromosomes in the GnomAD database, including 4,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.23 (4382 hom., cov: 33)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.599
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 15-88184520-A-T is Benign according to our data. Variant chr15-88184520-A-T is described in ClinVar as Benign. ClinVar VariationId is 1228998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	NM_001012338.3	MANE Select	c.249-221T>A		intron	N/A	NP_001012338.1
	NTRK3	NM_001375810.1		c.249-221T>A		intron	N/A	NP_001362739.1
	NTRK3	NM_001375811.1		c.249-221T>A		intron	N/A	NP_001362740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.249-221T>A		intron	N/A	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.249-221T>A		intron	N/A	ENSP00000453959.1
	NTRK3	ENST00000558676.5	TSL:1	c.249-221T>A		intron	N/A	ENSP00000453511.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34417 AN: 151994 Hom.: 4369 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.204

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.227 AC: 34470 AN: 152112 Hom.: 4382 Cov.: 33 AF XY: 0.224 AC XY: 16660 AN XY: 74370

African (AFR) AF: 0.331 AC: 13721 AN: 41478

American (AMR) AF: 0.230 AC: 3516 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3468

East Asian (EAS) AF: 0.141 AC: 727 AN: 5162

South Asian (SAS) AF: 0.307 AC: 1480 AN: 4820

European-Finnish (FIN) AF: 0.117 AC: 1236 AN: 10594

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.184 AC: 12476 AN: 67988

Other (OTH) AF: 0.206 AC: 434 AN: 2110

Alfa AF: 0.201 Hom.: 397

Bravo AF: 0.234

Asia WGS AF: 0.259 AC: 900 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.78
DANN	Benign	0.51
PhyloP100		-0.60
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: rs4887380; hg19: chr15-88727751;