15-87932935-A-C

Variant names:

• chr15-87932935-A-C
• rs1006046
• NM_001012338.3:c.1889+77T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001012338.3(NTRK3):​c.1889+77T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0517 in 1,475,410 control chromosomes in the GnomAD database, including 2,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (273 hom., cov: 32)
  • Exomes 𝑓: 0.051 (1993 hom.)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.545
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 15-87932935-A-C is Benign according to our data. Variant chr15-87932935-A-C is described in ClinVar as Benign. ClinVar VariationId is 1276265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	NM_001012338.3	MANE Select	c.1889+77T>G		intron	N/A	NP_001012338.1
	NTRK3	NM_001375810.1		c.1889+77T>G		intron	N/A	NP_001362739.1
	NTRK3	NM_001375811.1		c.1889+77T>G		intron	N/A	NP_001362740.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.1889+77T>G		intron	N/A	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.1865+77T>G		intron	N/A	ENSP00000453959.1
	NTRK3	ENST00000558676.5	TSL:1	c.1865+77T>G		intron	N/A	ENSP00000453511.1

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8368 AN: 152094 Hom.: 268 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.0541

GnomAD4 exome AF: 0.0513 AC: 67876 AN: 1323198 Hom.: 1993 AF XY: 0.0515 AC XY: 34174 AN XY: 663372

African (AFR) AF: 0.0761 AC: 2340 AN: 30752

American (AMR) AF: 0.0340 AC: 1436 AN: 42252

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 1555 AN: 25000

East Asian (EAS) AF: 0.000232 AC: 9 AN: 38808

South Asian (SAS) AF: 0.0414 AC: 3372 AN: 81490

European-Finnish (FIN) AF: 0.0245 AC: 1287 AN: 52502

Middle Eastern (MID) AF: 0.0613 AC: 261 AN: 4256

European-Non Finnish (NFE) AF: 0.0552 AC: 54750 AN: 992518

Other (OTH) AF: 0.0515 AC: 2866 AN: 55620

GnomAD4 genome AF: 0.0551 AC: 8392 AN: 152212 Hom.: 273 Cov.: 32 AF XY: 0.0522 AC XY: 3883 AN XY: 74430

African (AFR) AF: 0.0783 AC: 3253 AN: 41526

American (AMR) AF: 0.0445 AC: 681 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 240 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0341 AC: 164 AN: 4812

European-Finnish (FIN) AF: 0.0204 AC: 216 AN: 10606

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0538 AC: 3657 AN: 68010

Other (OTH) AF: 0.0535 AC: 113 AN: 2112

Alfa AF: 0.0563 Hom.: 512

Bravo AF: 0.0574

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.63
DANN	Benign	0.73
PhyloP100		-0.55
PromoterAI		0.0038	Neutral
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: rs1006046; hg19: chr15-88476166;