NM_014215.3:c.3601G>T

Variant names:

• chr1-156841455-C-A
• rs1002185894
• NM_014215.3:c.3601G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014215.3(INSRR):​c.3601G>T​(p.Val1201Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: INSRR NM_014215.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

INSRR (HGNC:6093): (insulin receptor related receptor) Enables transmembrane receptor protein tyrosine kinase activity. Involved in actin cytoskeleton reorganization; cellular response to alkaline pH; and protein autophosphorylation. Part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSRR	NM_014215.3	c.3601G>T	p.Val1201Leu	missense_variant	Exon 21 of 22	ENST00000368195.4	NP_055030.1
NTRK1	NM_001007792.1	c.10-626C>A		intron_variant	Intron 1 of 16		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSRR	ENST00000368195.4	c.3601G>T	p.Val1201Leu	missense_variant	Exon 21 of 22	1	NM_014215.3	ENSP00000357178.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3601G>T (p.V1201L) alteration is located in exon 21 (coding exon 21) of the INSRR gene. This alteration results from a G to T substitution at nucleotide position 3601, causing the valine (V) at amino acid position 1201 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.88		Loss of ubiquitination at K1203 (P = 0.1151);
MVP		0.92
MPC		0.32
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.78
gMVP		0.74
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1002185894; hg19: chr1-156811247; COSMIC: COSV100947285;