15-88256093-C-G

Variant names:

• chr15-88256093-C-G
• rs200822610
• NM_001012338.3:c.61G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012338.3(NTRK3):​c.61G>C​(p.Val21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. V21F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NTRK3 NM_001012338.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.577
• 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-AS1 (HGNC:27532): (NTRK3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0709635).

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.61G>C	p.Val21Leu	missense	Exon 3 of 20	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.61G>C	p.Val21Leu	missense	Exon 1 of 18	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.61G>C	p.Val21Leu	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.61G>C	p.Val21Leu	missense	Exon 3 of 20	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.61G>C	p.Val21Leu	missense	Exon 1 of 16	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.61G>C	p.Val21Leu	missense	Exon 1 of 14	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151012 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460926 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726774

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111428

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151012 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73684

African (AFR) AF: 0.0000244 AC: 1 AN: 41026

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67768

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.58
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.32	N
REVEL	Benign	0.10
Sift	Benign	0.67	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.37		Loss of helix (P = 0.1299)
MVP		0.33
MPC		0.44
ClinPred		0.10	T
GERP RS		1.2
PromoterAI		-0.054	Neutral
Varity_R		0.089
gMVP		0.34
Mutation Taster		=93/7	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: rs200822610; hg19: chr15-88799324;