NM_001012338.3:c.1488C>G

Variant names:

• chr15-88032954-G-C
• rs2229910
• NM_001012338.3:c.1488C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001012338.3(NTRK3):​c.1488C>G​(p.Ala496Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,611,594 control chromosomes in the GnomAD database, including 100,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A496A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.36 (10141 hom., cov: 27)
  • Exomes 𝑓: 0.35 (90415 hom.)
• Consequence: NTRK3 NM_001012338.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.466
• Publications: 27 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-88032954-G-C is Benign according to our data. Variant chr15-88032954-G-C is described in ClinVar as Benign. ClinVar VariationId is 1251369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.409 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.1488C>G	p.Ala496Ala	synonymous	Exon 14 of 20	NP_001012338.1
	NTRK3	NM_001375810.1		c.1488C>G	p.Ala496Ala	synonymous	Exon 12 of 18	NP_001362739.1
	NTRK3	NM_001375811.1		c.1488C>G	p.Ala496Ala	synonymous	Exon 12 of 17	NP_001362740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.1488C>G	p.Ala496Ala	synonymous	Exon 14 of 20	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.1464C>G	p.Ala488Ala	synonymous	Exon 11 of 16	ENSP00000453959.1
	NTRK3	ENST00000558676.5	TSL:1	c.1464C>G	p.Ala488Ala	synonymous	Exon 11 of 14	ENSP00000453511.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 54911 AN: 150672 Hom.: 10129 Cov.: 27

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.448

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.357

GnomAD2 exomes AF: 0.347 AC: 86645 AN: 249410 AF XY: 0.350

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.340

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.349 AC: 510182 AN: 1460804 Hom.: 90415 Cov.: 43 AF XY: 0.351 AC XY: 254768 AN XY: 726582

African (AFR) AF: 0.419 AC: 14013 AN: 33476

American (AMR) AF: 0.343 AC: 15281 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 10544 AN: 26098

East Asian (EAS) AF: 0.209 AC: 8285 AN: 39686

South Asian (SAS) AF: 0.391 AC: 33643 AN: 86056

European-Finnish (FIN) AF: 0.296 AC: 15800 AN: 53320

Middle Eastern (MID) AF: 0.461 AC: 2660 AN: 5764

European-Non Finnish (NFE) AF: 0.350 AC: 388486 AN: 1111482

Other (OTH) AF: 0.356 AC: 21470 AN: 60348

GnomAD4 genome AF: 0.364 AC: 54944 AN: 150790 Hom.: 10141 Cov.: 27 AF XY: 0.362 AC XY: 26626 AN XY: 73570

African (AFR) AF: 0.414 AC: 16953 AN: 40930

American (AMR) AF: 0.358 AC: 5433 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1391 AN: 3462

East Asian (EAS) AF: 0.220 AC: 1107 AN: 5036

South Asian (SAS) AF: 0.380 AC: 1805 AN: 4748

European-Finnish (FIN) AF: 0.288 AC: 3000 AN: 10428

Middle Eastern (MID) AF: 0.448 AC: 129 AN: 288

European-Non Finnish (NFE) AF: 0.357 AC: 24148 AN: 67710

Other (OTH) AF: 0.358 AC: 749 AN: 2092

Alfa AF: 0.292 Hom.: 1175

Bravo AF: 0.371

EpiCase AF: 0.362

EpiControl AF: 0.369

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	NTRK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.060
DANN	Benign	0.66
PhyloP100		-0.47
Mutation Taster		=97/3	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: rs2229910; hg19: chr15-88576185; COSMIC: COSV58110833;