NM_001012338.3:c.249-3923C>G

Variant names:

• chr15-88188222-G-C
• rs8042990
• NM_001012338.3:c.249-3923C>G

Variant summary

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

The NM_001012338.3(NTRK3):​c.249-3923C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,150 control chromosomes in the GnomAD database, including 8,479 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 0.33 (8479 hom., cov: 33)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 1 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 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.249-3923C>G		intron	N/A	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.249-3923C>G		intron	N/A	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.249-3923C>G		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.249-3923C>G		intron	N/A	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.249-3923C>G		intron	N/A	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.249-3923C>G		intron	N/A	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49967 AN: 152032 Hom.: 8464 Cov.: 33

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.309

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

GnomAD4 genome AF: 0.329 AC: 50024 AN: 152150 Hom.: 8479 Cov.: 33 AF XY: 0.327 AC XY: 24337 AN XY: 74372

African (AFR) AF: 0.409 AC: 16969 AN: 41494

American (AMR) AF: 0.249 AC: 3807 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1301 AN: 3472

East Asian (EAS) AF: 0.234 AC: 1208 AN: 5172

South Asian (SAS) AF: 0.316 AC: 1525 AN: 4826

European-Finnish (FIN) AF: 0.300 AC: 3178 AN: 10592

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21025 AN: 67990

Other (OTH) AF: 0.311 AC: 656 AN: 2108

Alfa AF: 0.180 Hom.: 356

Bravo AF: 0.327

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.44
PhyloP100		-1.1
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: rs8042990; hg19: chr15-88731453;