15-87925700-T-C

Variant names:

• chr15-87925700-T-C
• rs1078163
• NM_001012338.3:c.2133+3491A>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.2133+3491A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 186,064 control chromosomes in the GnomAD database, including 1,851 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 0.13 (1476 hom., cov: 33)
  • Exomes 𝑓: 0.15 (375 hom.)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.22 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	NM_001012338.3	MANE Select	c.2133+3491A>G		intron	N/A	NP_001012338.1
	NTRK3	NM_001375810.1		c.2133+3491A>G		intron	N/A	NP_001362739.1
	NTRK3	NM_001375811.1		c.2133+3491A>G		intron	N/A	NP_001362740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.2133+3491A>G		intron	N/A	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.2109+3491A>G		intron	N/A	ENSP00000453959.1
	NTRK3	ENST00000626019.2	TSL:5	c.2133+3491A>G		intron	N/A	ENSP00000486784.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19856 AN: 152148 Hom.: 1473 Cov.: 33

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.00 AC: 0 AN: 10 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.148 AC: 5008 AN: 33798 Hom.: 375 Cov.: 0 AF XY: 0.145 AC XY: 2259 AN XY: 15572

African (AFR) AF: 0.0789 AC: 93 AN: 1178

American (AMR) AF: 0.0931 AC: 76 AN: 816

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 306 AN: 2204

East Asian (EAS) AF: 0.140 AC: 904 AN: 6458

South Asian (SAS) AF: 0.262 AC: 74 AN: 282

European-Finnish (FIN) AF: 0.0556 AC: 1 AN: 18

Middle Eastern (MID) AF: 0.250 AC: 56 AN: 224

European-Non Finnish (NFE) AF: 0.156 AC: 3085 AN: 19810

Other (OTH) AF: 0.147 AC: 413 AN: 2808

GnomAD4 genome AF: 0.131 AC: 19878 AN: 152266 Hom.: 1476 Cov.: 33 AF XY: 0.130 AC XY: 9689 AN XY: 74466

African (AFR) AF: 0.0909 AC: 3778 AN: 41564

American (AMR) AF: 0.104 AC: 1587 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 463 AN: 3470

East Asian (EAS) AF: 0.144 AC: 746 AN: 5174

South Asian (SAS) AF: 0.231 AC: 1114 AN: 4822

European-Finnish (FIN) AF: 0.0896 AC: 951 AN: 10614

Middle Eastern (MID) AF: 0.195 AC: 57 AN: 292

European-Non Finnish (NFE) AF: 0.159 AC: 10802 AN: 68012

Other (OTH) AF: 0.132 AC: 279 AN: 2114

Alfa AF: 0.146 Hom.: 3263

Bravo AF: 0.127

Asia WGS AF: 0.192 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.69
PhyloP100		-0.39
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: rs1078163; hg19: chr15-88468931;