NM_005544.3:c.3489A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005544.3(IRS1):​c.3489A>C​(p.Pro1163Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,876 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 6 hom., cov: 33)
Exomes 𝑓: 0.00099 ( 10 hom. )

Consequence

IRS1
NM_005544.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -6.68

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: Benign. The variant received -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 2-226795250-T-G is Benign according to our data. Variant chr2-226795250-T-G is described in ClinVar as [Benign]. Clinvar id is 722785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-6.68 with no splicing effect.
BS2
High AC in GnomAd4 at 217 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRS1NM_005544.3 linkc.3489A>C p.Pro1163Pro synonymous_variant Exon 1 of 2 ENST00000305123.6 NP_005535.1 P35568
IRS1XM_047444223.1 linkc.3489A>C p.Pro1163Pro synonymous_variant Exon 1 of 2 XP_047300179.1
IRS1XM_047444224.1 linkc.3489A>C p.Pro1163Pro synonymous_variant Exon 1 of 2 XP_047300180.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRS1ENST00000305123.6 linkc.3489A>C p.Pro1163Pro synonymous_variant Exon 1 of 2 1 NM_005544.3 ENSP00000304895.4 P35568
ENSG00000272622ENST00000727652.1 linkn.166+410T>G intron_variant Intron 1 of 3
ENSG00000272622ENST00000727654.1 linkn.71+307T>G intron_variant Intron 1 of 3
IRS1ENST00000498335.1 linkn.-4A>C upstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00143
AC:
217
AN:
151994
Hom.:
6
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0160
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000368
Gnomad OTH
AF:
0.00240
GnomAD2 exomes
AF:
0.00217
AC:
545
AN:
251100
AF XY:
0.00203
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00101
Gnomad ASJ exome
AF:
0.00338
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0173
Gnomad NFE exome
AF:
0.000705
Gnomad OTH exome
AF:
0.00310
GnomAD4 exome
AF:
0.000993
AC:
1452
AN:
1461764
Hom.:
10
Cov.:
41
AF XY:
0.000972
AC XY:
707
AN XY:
727186
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00103
AC:
46
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00325
AC:
85
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000128
AC:
11
AN:
86258
European-Finnish (FIN)
AF:
0.0166
AC:
885
AN:
53300
Middle Eastern (MID)
AF:
0.000520
AC:
3
AN:
5768
European-Non Finnish (NFE)
AF:
0.000307
AC:
341
AN:
1112006
Other (OTH)
AF:
0.00134
AC:
81
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
94
188
283
377
471
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.00143
AC:
217
AN:
152112
Hom.:
6
Cov.:
33
AF XY:
0.00214
AC XY:
159
AN XY:
74394
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41516
American (AMR)
AF:
0.000262
AC:
4
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.00317
AC:
11
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5148
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.0160
AC:
170
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.000368
AC:
25
AN:
67956
Other (OTH)
AF:
0.00237
AC:
5
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
9
18
26
35
44
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
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:
0.000853
Hom.:
1
Bravo
AF:
0.000317
EpiCase
AF:
0.000600
EpiControl
AF:
0.000415

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Dec 31, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.89
DANN
Benign
0.38
PhyloP100
-6.7
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: rs143317854; hg19: chr2-227659966; API