rs370504033

chr1-156881585-C-Achr1-156881585-C-Gchr1-156881585-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002529.4(NTRK1):c.2334C>A(p.His778Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H778H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.121

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.2334C>A	p.His778Gln	missense_variant	17/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.2316C>A	p.His772Gln	missense_variant	16/16
NTRK1	NM_001007792.1	c.2226C>A	p.His742Gln	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.2334C>A	p.His778Gln	missense_variant	17/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243176 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	4.1
Dann	Benign	0.91
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	-0.065	T
MutationTaster	Benign	0.91	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.066	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.67, 0.18	.;P;B;.
Vest4		0.35
MutPred		0.51		.;.;Gain of MoRF binding (P = 0.0822);.;
MVP		0.81
MPC		0.70
ClinPred		0.98	D
GERP RS		-4.0
Varity_R		0.52
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs370504033; hg19: chr1-156851377;