rs1128994

Variant names:

• chr15-88137453-G-A
• rs1128994
• NM_001012338.3:c.573C>T

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.573C>T​(p.Asn191Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,770 control chromosomes in the GnomAD database, including 59,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6598 hom., cov: 33)
  • Exomes 𝑓: 0.27 (52988 hom.)
• Consequence: NTRK3 NM_001012338.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.570
• Publications: 19 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=-0.75).
• BP6: Variant 15-88137453-G-A is Benign according to our data. Variant chr15-88137453-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 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.573C>T	p.Asn191Asn	synonymous	Exon 7 of 20	NP_001012338.1
	NTRK3	NM_001375810.1		c.573C>T	p.Asn191Asn	synonymous	Exon 5 of 18	NP_001362739.1
	NTRK3	NM_001375811.1		c.573C>T	p.Asn191Asn	synonymous	Exon 5 of 17	NP_001362740.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.573C>T	p.Asn191Asn	synonymous	Exon 7 of 20	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.573C>T	p.Asn191Asn	synonymous	Exon 5 of 16	ENSP00000453959.1
	NTRK3	ENST00000558676.5	TSL:1	c.573C>T	p.Asn191Asn	synonymous	Exon 5 of 14	ENSP00000453511.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43764 AN: 152022 Hom.: 6584 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.281

GnomAD2 exomes AF: 0.257 AC: 64465 AN: 251146 AF XY: 0.257

Gnomad AFR exome AF: 0.377

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.259

GnomAD4 exome AF: 0.267 AC: 389969 AN: 1461630 Hom.: 52988 Cov.: 37 AF XY: 0.267 AC XY: 194245 AN XY: 727110

African (AFR) AF: 0.383 AC: 12836 AN: 33472

American (AMR) AF: 0.155 AC: 6911 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8958 AN: 26134

East Asian (EAS) AF: 0.202 AC: 8002 AN: 39700

South Asian (SAS) AF: 0.268 AC: 23144 AN: 86242

European-Finnish (FIN) AF: 0.247 AC: 13160 AN: 53368

Middle Eastern (MID) AF: 0.324 AC: 1855 AN: 5726

European-Non Finnish (NFE) AF: 0.268 AC: 298287 AN: 1111882

Other (OTH) AF: 0.278 AC: 16816 AN: 60388

GnomAD4 genome AF: 0.288 AC: 43819 AN: 152140 Hom.: 6598 Cov.: 33 AF XY: 0.285 AC XY: 21191 AN XY: 74380

African (AFR) AF: 0.372 AC: 15446 AN: 41500

American (AMR) AF: 0.197 AC: 3013 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1156 AN: 3472

East Asian (EAS) AF: 0.228 AC: 1178 AN: 5160

South Asian (SAS) AF: 0.266 AC: 1280 AN: 4818

European-Finnish (FIN) AF: 0.239 AC: 2527 AN: 10594

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.269 AC: 18302 AN: 67974

Other (OTH) AF: 0.284 AC: 601 AN: 2114

Alfa AF: 0.285 Hom.: 4050

Bravo AF: 0.289

Asia WGS AF: 0.259 AC: 902 AN: 3478

EpiCase AF: 0.271

EpiControl AF: 0.262

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	-0.75
CADD	Benign	3.9
DANN	Benign	0.63
PhyloP100		-0.57
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: rs1128994; hg19: chr15-88680684; COSMIC: COSV58119651; COSMIC: COSV58119651;