15-88028303-A-G

Variant names:

• chr15-88028303-A-G
• rs4887348
• NM_001012338.3:c.1585+4554T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001012338.3(NTRK3):​c.1585+4554T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 152,120 control chromosomes in the GnomAD database, including 4,281 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 0.22 (4281 hom., cov: 32)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 10 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	NM_001012338.3	MANE Select	c.1585+4554T>C		intron	N/A	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.1585+4554T>C		intron	N/A	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.1585+4554T>C		intron	N/A	NP_001362740.1	X5D7M5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.1585+4554T>C		intron	N/A	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.1561+4554T>C		intron	N/A	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.1561+4554T>C		intron	N/A	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33964 AN: 152002 Hom.: 4277 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.248

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

GnomAD4 genome AF: 0.223 AC: 33965 AN: 152120 Hom.: 4281 Cov.: 32 AF XY: 0.225 AC XY: 16719 AN XY: 74350

African (AFR) AF: 0.112 AC: 4637 AN: 41536

American (AMR) AF: 0.271 AC: 4144 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1103 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1092 AN: 5162

South Asian (SAS) AF: 0.335 AC: 1609 AN: 4796

European-Finnish (FIN) AF: 0.197 AC: 2089 AN: 10598

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18474 AN: 67952

Other (OTH) AF: 0.247 AC: 523 AN: 2114

Alfa AF: 0.257 Hom.: 9667

Bravo AF: 0.220

Asia WGS AF: 0.282 AC: 980 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.23
DANN	Benign	0.58
PhyloP100		-1.0
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: rs4887348; hg19: chr15-88571534;