chr1-156840887-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014215.3(INSRR):​c.3880G>T​(p.Gly1294Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

INSRR
NM_014215.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0120
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061247975).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INSRRNM_014215.3 linkuse as main transcriptc.3880G>T p.Gly1294Cys missense_variant 22/22 ENST00000368195.4
NTRK1NM_001007792.1 linkuse as main transcriptc.10-1194C>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INSRRENST00000368195.4 linkuse as main transcriptc.3880G>T p.Gly1294Cys missense_variant 22/221 NM_014215.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152188
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.0000882
AC:
22
AN:
249398
Hom.:
0
AF XY:
0.0000592
AC XY:
8
AN XY:
135038
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000406
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000472
Gnomad NFE exome
AF:
0.0000532
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.000105
AC:
154
AN:
1460942
Hom.:
0
Cov.:
31
AF XY:
0.0000881
AC XY:
64
AN XY:
726780
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000105
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152306
Hom.:
0
Cov.:
31
AF XY:
0.000107
AC XY:
8
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.000128
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsOct 12, 2022The c.3880G>T (p.G1294C) alteration is located in exon 22 (coding exon 22) of the INSRR gene. This alteration results from a G to T substitution at nucleotide position 3880, causing the glycine (G) at amino acid position 1294 to be replaced by a cysteine (C). 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
Benign
0.095
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.17
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.66
T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.061
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.69
N
REVEL
Benign
0.15
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0070
D
Polyphen
0.73
P
Vest4
0.26
MVP
0.85
MPC
0.19
ClinPred
0.089
T
GERP RS
2.3
Varity_R
0.15
gMVP
0.46

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs536346142; hg19: chr1-156810679; API