chr15-88126151-G-C

Variant names:

• chr15-88126151-G-C
• rs3825882
• NM_001012338.3:c.1396+120C>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.1396+120C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 753,346 control chromosomes in the GnomAD database, including 99,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24016 hom., cov: 32)
  • Exomes 𝑓: 0.49 (75189 hom.)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.595
• Publications: 5 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=-0.9).
• BP6: Variant 15-88126151-G-C is Benign according to our data. Variant chr15-88126151-G-C is described in ClinVar as Benign. ClinVar VariationId is 1277211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 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.1396+120C>G		intron	N/A	NP_001012338.1
	NTRK3	NM_001375810.1		c.1396+120C>G		intron	N/A	NP_001362739.1
	NTRK3	NM_001375811.1		c.1396+120C>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.1396+120C>G		intron	N/A	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.1372+120C>G		intron	N/A	ENSP00000453959.1
	NTRK3	ENST00000558676.5	TSL:1	c.1372+120C>G		intron	N/A	ENSP00000453511.1

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83032 AN: 151884 Hom.: 23972 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.502

GnomAD4 exome AF: 0.494 AC: 296968 AN: 601344 Hom.: 75189 AF XY: 0.500 AC XY: 161044 AN XY: 322130

African (AFR) AF: 0.750 AC: 12327 AN: 16430

American (AMR) AF: 0.403 AC: 13663 AN: 33934

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 10976 AN: 19324

East Asian (EAS) AF: 0.361 AC: 11176 AN: 30926

South Asian (SAS) AF: 0.596 AC: 37385 AN: 62734

European-Finnish (FIN) AF: 0.408 AC: 18211 AN: 44596

Middle Eastern (MID) AF: 0.552 AC: 2258 AN: 4092

European-Non Finnish (NFE) AF: 0.489 AC: 175071 AN: 358162

Other (OTH) AF: 0.511 AC: 15901 AN: 31146

GnomAD4 genome AF: 0.547 AC: 83133 AN: 152002 Hom.: 24016 Cov.: 32 AF XY: 0.540 AC XY: 40154 AN XY: 74294

African (AFR) AF: 0.751 AC: 31113 AN: 41446

American (AMR) AF: 0.433 AC: 6619 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1903 AN: 3470

East Asian (EAS) AF: 0.366 AC: 1889 AN: 5168

South Asian (SAS) AF: 0.600 AC: 2886 AN: 4814

European-Finnish (FIN) AF: 0.396 AC: 4186 AN: 10564

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32881 AN: 67950

Other (OTH) AF: 0.509 AC: 1071 AN: 2106

Alfa AF: 0.384 Hom.: 1039

Bravo AF: 0.552

Asia WGS AF: 0.527 AC: 1836 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.3
DANN	Benign	0.35
PhyloP100		0.59
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: rs3825882; hg19: chr15-88669382; COSMIC: COSV58150661;