1-156840978-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_014215.3(INSRR):​c.3789G>A​(p.Pro1263Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

INSRR
NM_014215.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.82

Publications

0 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 1-156840978-C-T is Benign according to our data. Variant chr1-156840978-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1675386.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-5.82 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INSRRNM_014215.3 linkc.3789G>A p.Pro1263Pro synonymous_variant Exon 22 of 22 ENST00000368195.4 NP_055030.1 P14616
NTRK1NM_001007792.1 linkc.10-1103C>T intron_variant Intron 1 of 16 NP_001007793.1 P04629-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INSRRENST00000368195.4 linkc.3789G>A p.Pro1263Pro synonymous_variant Exon 22 of 22 1 NM_014215.3 ENSP00000357178.3 P14616

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000607
AC:
15
AN:
247312
AF XY:
0.0000671
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000175
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000716
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000650
AC:
95
AN:
1461318
Hom.:
0
Cov.:
32
AF XY:
0.0000647
AC XY:
47
AN XY:
726908
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33474
American (AMR)
AF:
0.000179
AC:
8
AN:
44660
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39684
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86140
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53332
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.0000765
AC:
85
AN:
1111816
Other (OTH)
AF:
0.00
AC:
0
AN:
60324
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74356
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000823
Hom.:
0
Bravo
AF:
0.0000718
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000595

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Mar 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

INSRR: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
0.052
DANN
Benign
0.80
PhyloP100
-5.8
Mutation Taster
=100/0
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

Publications

Other links and lift over

dbSNP: rs370144321; hg19: chr1-156810770; COSMIC: COSV100948251; API