NM_001012338.3:c.1488C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_001012338.3(NTRK3):​c.1488C>T​(p.Ala496Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,611,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A496A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: NTRK3 NM_001012338.3 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 75 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	NM_001012338.3	MANE Select	c.1488C>T	p.Ala496Ala	synonymous	Exon 14 of 20	NP_001012338.1
	NTRK3	NM_001375810.1		c.1488C>T	p.Ala496Ala	synonymous	Exon 12 of 18	NP_001362739.1
	NTRK3	NM_001375811.1		c.1488C>T	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>T	p.Ala496Ala	synonymous	Exon 14 of 20	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.1464C>T	p.Ala488Ala	synonymous	Exon 11 of 16	ENSP00000453959.1
	NTRK3	ENST00000558676.5	TSL:1	c.1464C>T	p.Ala488Ala	synonymous	Exon 11 of 14	ENSP00000453511.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150858 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000682 AC: 17 AN: 249410 AF XY: 0.0000965

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1460970 Hom.: 0 Cov.: 43 AF XY: 0.0000619 AC XY: 45 AN XY: 726676

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000449 AC: 2 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86076

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53346

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111576

Other (OTH) AF: 0.0000994 AC: 6 AN: 60352

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150976 Hom.: 0 Cov.: 27 AF XY: 0.0000407 AC XY: 3 AN XY: 73670

African (AFR) AF: 0.0000244 AC: 1 AN: 41004

American (AMR) AF: 0.0000658 AC: 1 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5038

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67760

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.00 Hom.: 1175

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.44
DANN	Benign	0.89
PhyloP100		-0.47

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: COSV58122657;