rs6334

Variant names:

• chr1-156876441-G-A
• rs6334
• NM_002529.4:c.1674G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156876441-G-A
• chr1-156876441-G-C
• chr1-156876441-G-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_002529.4(NTRK1):​c.1674G>A​(p.Gln558Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,668 control chromosomes in the GnomAD database, including 39,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3219 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36528 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.221
• Publications: 52 publications found

Genes affected

NTRK1 (HGNC:8031): (neurotrophic receptor tyrosine kinase 1) This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

NTRK1 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-156876441-G-A is Benign according to our data. Variant chr1-156876441-G-A is described in ClinVar as Benign. ClinVar VariationId is 292889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.221 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002529.4. 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
	NTRK1	NM_002529.4	MANE Select	c.1674G>A	p.Gln558Gln	synonymous	Exon 14 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1656G>A	p.Gln552Gln	synonymous	Exon 13 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.1566G>A	p.Gln522Gln	synonymous	Exon 14 of 17	NP_001007793.1	P04629-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.1674G>A	p.Gln558Gln	synonymous	Exon 14 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.1656G>A	p.Gln552Gln	synonymous	Exon 13 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.1665G>A	p.Gln555Gln	synonymous	Exon 13 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30552 AN: 152072 Hom.: 3221 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.220 AC: 55246 AN: 250768 AF XY: 0.223

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.221 AC: 322889 AN: 1461478 Hom.: 36528 Cov.: 41 AF XY: 0.222 AC XY: 161355 AN XY: 727046

African (AFR) AF: 0.131 AC: 4402 AN: 33478

American (AMR) AF: 0.216 AC: 9676 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5121 AN: 26136

East Asian (EAS) AF: 0.356 AC: 14121 AN: 39694

South Asian (SAS) AF: 0.235 AC: 20244 AN: 86254

European-Finnish (FIN) AF: 0.201 AC: 10674 AN: 53102

Middle Eastern (MID) AF: 0.214 AC: 1232 AN: 5766

European-Non Finnish (NFE) AF: 0.219 AC: 243886 AN: 1111952

Other (OTH) AF: 0.224 AC: 13533 AN: 60382

GnomAD4 genome AF: 0.201 AC: 30560 AN: 152190 Hom.: 3219 Cov.: 32 AF XY: 0.203 AC XY: 15080 AN XY: 74398

African (AFR) AF: 0.138 AC: 5749 AN: 41534

American (AMR) AF: 0.226 AC: 3462 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 724 AN: 3470

East Asian (EAS) AF: 0.345 AC: 1785 AN: 5170

South Asian (SAS) AF: 0.241 AC: 1162 AN: 4828

European-Finnish (FIN) AF: 0.202 AC: 2144 AN: 10600

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14806 AN: 67980

Other (OTH) AF: 0.213 AC: 449 AN: 2108

Alfa AF: 0.206 Hom.: 7321

Bravo AF: 0.200

Asia WGS AF: 0.283 AC: 984 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary insensitivity to pain with anhidrosis (5)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.2
DANN	Benign	0.93
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs6334; hg19: chr1-156846233; COSMIC: COSV62323674; COSMIC: COSV62323674;