15-88256006-C-G

Variant names:

• chr15-88256006-C-G
• rs907290552
• NM_001012338.3:c.148G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001012338.3(NTRK3):​c.148G>C​(p.Asp50His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D50N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NTRK3 NM_001012338.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60
• 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-AS1 (HGNC:27532): (NTRK3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33511367).

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.148G>C	p.Asp50His	missense	Exon 3 of 20	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.148G>C	p.Asp50His	missense	Exon 1 of 18	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.148G>C	p.Asp50His	missense	Exon 1 of 17	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.148G>C	p.Asp50His	missense	Exon 3 of 20	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.148G>C	p.Asp50His	missense	Exon 1 of 16	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.148G>C	p.Asp50His	missense	Exon 1 of 14	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.014
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.90	L
PhyloP100		2.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.51
Sift	Benign	0.079	T
Sift4G	Benign	0.11	T
Polyphen		0.91	P
Vest4		0.36
MutPred		0.47		Loss of disorder (P = 0.1134)
MVP		0.65
MPC		1.3
ClinPred		0.65	D
GERP RS		2.9
PromoterAI		-0.015	Neutral
Varity_R		0.13
gMVP		0.65
Mutation Taster		=80/20	polymorphism

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: rs907290552; hg19: chr15-88799237;