chr15-88256071-G-A

Variant names:

• chr15-88256071-G-A
• rs201985502
• NM_001012338.3:c.83C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001012338.3(NTRK3):​c.83C>T​(p.Ser28Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000161 in 1,613,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S28S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NTRK3 NM_001012338.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18083373).
• BS2: High AC in GnomAd4 at 18 AD gene.

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.83C>T	p.Ser28Phe	missense	Exon 3 of 20	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.83C>T	p.Ser28Phe	missense	Exon 1 of 18	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.83C>T	p.Ser28Phe	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.83C>T	p.Ser28Phe	missense	Exon 3 of 20	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.83C>T	p.Ser28Phe	missense	Exon 1 of 16	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.83C>T	p.Ser28Phe	missense	Exon 1 of 14	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151568 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

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: 0.000177

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251280 AF XY: 0.0000957

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1461690 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 117 AN XY: 727146

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000210 AC: 233 AN: 1111912

Other (OTH) AF: 0.0000828 AC: 5 AN: 60382

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151676 Hom.: 0 Cov.: 30 AF XY: 0.0000945 AC XY: 7 AN XY: 74098

African (AFR) AF: 0.0000484 AC: 2 AN: 41330

American (AMR) AF: 0.000131 AC: 2 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67898

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.44
MVP		0.63
MPC		1.2
ClinPred		0.21	T
GERP RS		3.9
PromoterAI		-0.047	Neutral
Varity_R		0.21
gMVP		0.60
Mutation Taster		=46/54	disease causing

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: rs201985502; hg19: chr15-88799302;