rs56320207

Variant names:

• chr1-156874985-G-A
• rs56320207
• NM_002529.4:c.1331G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156874985-G-A
• chr1-156874985-G-C
• chr1-156874985-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002529.4(NTRK1):​c.1331G>A​(p.Arg444Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,750 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (19 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (31 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.38
• Publications: 11 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074874163).
• BP6: Variant 1-156874985-G-A is Benign according to our data. Variant chr1-156874985-G-A is described in ClinVar as Benign. ClinVar VariationId is 292886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00934 (1421/152188) while in subpopulation AFR AF = 0.0326 (1355/41512). AF 95% confidence interval is 0.0312. There are 19 homozygotes in GnomAd4. There are 668 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

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.1331G>A	p.Arg444Gln	missense	Exon 11 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1313G>A	p.Arg438Gln	missense	Exon 10 of 16	NP_001012331.1
	NTRK1	NM_001007792.1		c.1223G>A	p.Arg408Gln	missense	Exon 11 of 17	NP_001007793.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.1331G>A	p.Arg444Gln	missense	Exon 11 of 17	ENSP00000431418.1
	NTRK1	ENST00000368196.7	TSL:1	c.1313G>A	p.Arg438Gln	missense	Exon 10 of 16	ENSP00000357179.3
	NTRK1	ENST00000358660.3	TSL:2	c.1313G>A	p.Arg438Gln	missense	Exon 10 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1418 AN: 152070 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00265 AC: 666 AN: 251462 AF XY: 0.00185

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00107 AC: 1565 AN: 1461562 Hom.: 31 Cov.: 32 AF XY: 0.000912 AC XY: 663 AN XY: 727112

African (AFR) AF: 0.0367 AC: 1227 AN: 33464

American (AMR) AF: 0.00143 AC: 64 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000900 AC: 100 AN: 1111720

Other (OTH) AF: 0.00252 AC: 152 AN: 60388

GnomAD4 genome AF: 0.00934 AC: 1421 AN: 152188 Hom.: 19 Cov.: 31 AF XY: 0.00898 AC XY: 668 AN XY: 74400

African (AFR) AF: 0.0326 AC: 1355 AN: 41512

American (AMR) AF: 0.00288 AC: 44 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00344 Hom.: 20

Bravo AF: 0.0109

ESP6500AA AF: 0.0318 AC: 140

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00326 AC: 396

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary insensitivity to pain with anhidrosis (5)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.4
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.10	B
Vest4		0.17
MVP		0.85
MPC		0.28
ClinPred		0.0034	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.38
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56320207; hg19: chr1-156844777; COSMIC: COSV62328913;