NM_005544.3:c.3286C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_005544.3(IRS1):​c.3286C>G​(p.Arg1096Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,414 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

IRS1
NM_005544.3 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Publications

1 publications found
Variant links:
Genes affected
IRS1 (HGNC:6125): (insulin receptor substrate 1) This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.821
BS2
High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRS1NM_005544.3 linkc.3286C>G p.Arg1096Gly missense_variant Exon 1 of 2 ENST00000305123.6 NP_005535.1 P35568
IRS1XM_047444223.1 linkc.3286C>G p.Arg1096Gly missense_variant Exon 1 of 2 XP_047300179.1
IRS1XM_047444224.1 linkc.3286C>G p.Arg1096Gly missense_variant Exon 1 of 2 XP_047300180.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRS1ENST00000305123.6 linkc.3286C>G p.Arg1096Gly missense_variant Exon 1 of 2 1 NM_005544.3 ENSP00000304895.4 P35568
ENSG00000272622ENST00000727652.1 linkn.166+613G>C intron_variant Intron 1 of 3
ENSG00000272622ENST00000727654.1 linkn.71+510G>C intron_variant Intron 1 of 3
IRS1ENST00000498335.1 linkn.-207C>G upstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000279
AC:
7
AN:
250616
AF XY:
0.0000369
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000619
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461206
Hom.:
0
Cov.:
42
AF XY:
0.0000220
AC XY:
16
AN XY:
726926
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52746
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000306
AC:
34
AN:
1112004
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
2
4
7
9
11
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:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41450
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:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
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
Jan 17, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3286C>G (p.R1096G) alteration is located in exon 1 (coding exon 1) of the IRS1 gene. This alteration results from a C to G substitution at nucleotide position 3286, causing the arginine (R) at amino acid position 1096 to be replaced by a glycine (G). 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
0.89
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.87
D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Uncertain
0.28
D
MutationAssessor
Uncertain
2.5
M
PhyloP100
1.8
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.69
MutPred
0.50
Loss of MoRF binding (P = 0.0325);
MVP
0.94
MPC
1.1
ClinPred
0.95
D
GERP RS
2.3
Varity_R
0.67
gMVP
0.60
Mutation Taster
=64/36
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: rs199554914; hg19: chr2-227660169; API