NM_002529.4:c.1908G>A

Variant names:

• chr1-156879224-G-A
• rs17838192
• NM_002529.4:c.1908G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_002529.4(NTRK1):​c.1908G>A​(p.Ala636Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,614,056 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (10 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -8.23
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-156879224-G-A is Benign according to our data. Variant chr1-156879224-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 380670.
• BP7: Synonymous conserved (PhyloP=-8.23 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.1908G>A	p.Ala636Ala	synonymous	Exon 15 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.1890G>A	p.Ala630Ala	synonymous	Exon 14 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.1800G>A	p.Ala600Ala	synonymous	Exon 15 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.1908G>A	p.Ala636Ala	synonymous	Exon 15 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.1890G>A	p.Ala630Ala	synonymous	Exon 14 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.1899G>A	p.Ala633Ala	synonymous	Exon 14 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00169 AC: 422 AN: 249888 AF XY: 0.00172

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00538

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00241 AC: 3526 AN: 1461780 Hom.: 10 Cov.: 33 AF XY: 0.00237 AC XY: 1720 AN XY: 727202

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00619 AC: 330 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00271 AC: 3017 AN: 1111988

Other (OTH) AF: 0.00247 AC: 149 AN: 60388

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152276 Hom.: 0 Cov.: 31 AF XY: 0.00189 AC XY: 141 AN XY: 74462

African (AFR) AF: 0.000602 AC: 25 AN: 41556

American (AMR) AF: 0.00170 AC: 26 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00241 AC: 164 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	2	Hereditary insensitivity to pain with anhidrosis (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.3
DANN	Benign	0.59
PhyloP100		-8.2
Mutation Taster		=98/2	polymorphism

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: rs17838192; hg19: chr1-156849016;