15-88256154-C-T

Variant names:

• chr15-88256154-C-T
• rs140166305
• NM_001012338.3:c.-1G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001012338.3(NTRK3):​c.-1G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,598,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: NTRK3 NM_001012338.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.18
• Publications: 1 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-88256154-C-T is Benign according to our data. Variant chr15-88256154-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3041033.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 153 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.-1G>A		5_prime_UTR	Exon 3 of 20	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.-1G>A		5_prime_UTR	Exon 1 of 18	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.-1G>A		5_prime_UTR	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.-1G>A		5_prime_UTR	Exon 3 of 20	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.-1G>A		5_prime_UTR	Exon 1 of 16	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.-1G>A		5_prime_UTR	Exon 1 of 14	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 153 AN: 147628 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000351

Gnomad AMI AF: 0.0123

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.00143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00109 AC: 264 AN: 243086 AF XY: 0.00101

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00184

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00165 AC: 2390 AN: 1451202 Hom.: 2 Cov.: 33 AF XY: 0.00160 AC XY: 1157 AN XY: 721960

African (AFR) AF: 0.000180 AC: 6 AN: 33344

American (AMR) AF: 0.000337 AC: 15 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39490

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86116

European-Finnish (FIN) AF: 0.00167 AC: 78 AN: 46730

Middle Eastern (MID) AF: 0.000538 AC: 3 AN: 5576

European-Non Finnish (NFE) AF: 0.00199 AC: 2212 AN: 1109350

Other (OTH) AF: 0.00100 AC: 60 AN: 60024

GnomAD4 genome AF: 0.00104 AC: 153 AN: 147730 Hom.: 1 Cov.: 28 AF XY: 0.000946 AC XY: 68 AN XY: 71898

African (AFR) AF: 0.000350 AC: 14 AN: 39960

American (AMR) AF: 0.000135 AC: 2 AN: 14796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 4932

South Asian (SAS) AF: 0.000440 AC: 2 AN: 4544

European-Finnish (FIN) AF: 0.00143 AC: 14 AN: 9820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00164 AC: 110 AN: 67018

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00109

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NTRK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		2.2
PromoterAI		0.17	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140166305; hg19: chr15-88799385; COSMIC: COSV100446016; COSMIC: COSV100446016;