15-88256113-C-G

Variant names:

• chr15-88256113-C-G
• NM_001012338.3:c.41G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001012338.3(NTRK3):​c.41G>C​(p.Arg14Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R14Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NTRK3 NM_001012338.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.31

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.41G>C	p.Arg14Pro	missense_variant	Exon 3 of 20	ENST00000629765.3	NP_001012338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3	c.41G>C	p.Arg14Pro	missense_variant	Exon 3 of 20	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460966 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;T;.;T;.;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;.;D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.90	L;L;L;L;L;.;L;.;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.81	N;.;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.19	T;.;T;T;T;.;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;.;.;.;.;.;.
Vest4		0.67
MutPred		0.52		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.78
MPC		1.3
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.55
gMVP		0.58

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-88799344;