1-156841431-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_014215.3(INSRR):c.3625G>A(p.Gly1209Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000088 in 1,613,780 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: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000094 ( 0 hom. )
Consequence
INSRR
NM_014215.3 missense
NM_014215.3 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 6.15
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.893
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
INSRR | NM_014215.3 | c.3625G>A | p.Gly1209Arg | missense_variant | 21/22 | ENST00000368195.4 | NP_055030.1 | |
NTRK1 | NM_001007792.1 | c.10-650C>T | intron_variant | NP_001007793.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
INSRR | ENST00000368195.4 | c.3625G>A | p.Gly1209Arg | missense_variant | 21/22 | 1 | NM_014215.3 | ENSP00000357178 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151966Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251372Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135866
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GnomAD4 exome AF: 0.0000937 AC: 137AN: 1461814Hom.: 0 Cov.: 33 AF XY: 0.0000894 AC XY: 65AN XY: 727222
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 151966Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4AN XY: 74218
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2021 | The c.3625G>A (p.G1209R) alteration is located in exon 21 (coding exon 21) of the INSRR gene. This alteration results from a G to A substitution at nucleotide position 3625, causing the glycine (G) at amino acid position 1209 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at G1209 (P = 0.0219);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at