X-108733295-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001379150.1(IRS4):ā€‹c.3050T>Cā€‹(p.Ile1017Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000579 in 1,209,968 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000089 ( 0 hom., 1 hem., cov: 23)
Exomes š‘“: 0.0000055 ( 0 hom. 2 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.91
Variant links:
Genes affected
IRS4 (HGNC:6128): (insulin receptor substrate 4) IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IRS4NM_001379150.1 linkuse as main transcriptc.3050T>C p.Ile1017Thr missense_variant 1/2 ENST00000372129.4 NP_001366079.1
IRS4NM_003604.2 linkuse as main transcriptc.3050T>C p.Ile1017Thr missense_variant 1/1 NP_003595.1 O14654
IRS4XM_011531061.2 linkuse as main transcriptc.3050T>C p.Ile1017Thr missense_variant 1/3 XP_011529363.1
IRS4XM_006724713.4 linkuse as main transcriptc.3050T>C p.Ile1017Thr missense_variant 1/2 XP_006724776.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IRS4ENST00000372129.4 linkuse as main transcriptc.3050T>C p.Ile1017Thr missense_variant 1/26 NM_001379150.1 ENSP00000361202.3 A0A804CF45
IRS4ENST00000564206.2 linkuse as main transcriptc.3050T>C p.Ile1017Thr missense_variant 1/16 ENSP00000505547.1 O14654

Frequencies

GnomAD3 genomes
AF:
0.00000894
AC:
1
AN:
111809
Hom.:
0
Cov.:
23
AF XY:
0.0000294
AC XY:
1
AN XY:
33991
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:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000545
AC:
1
AN:
183491
Hom.:
0
AF XY:
0.0000147
AC XY:
1
AN XY:
67919
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000546
AC:
6
AN:
1098159
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
2
AN XY:
363513
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000331
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000356
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000894
AC:
1
AN:
111809
Hom.:
0
Cov.:
23
AF XY:
0.0000294
AC XY:
1
AN XY:
33991
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189

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 GeneticsApr 16, 2024The c.3050T>C (p.I1017T) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a T to C substitution at nucleotide position 3050, causing the isoleucine (I) at amino acid position 1017 to be replaced by a threonine (T). 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
0.24
BayesDel_addAF
Benign
-0.074
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.56
T
M_CAP
Benign
0.0072
T
MetaRNN
Uncertain
0.66
D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.0
L
PrimateAI
Benign
0.45
T
PROVEAN
Benign
1.3
N
REVEL
Benign
0.22
Sift
Benign
0.45
T
Sift4G
Benign
0.36
T
Polyphen
0.15
B
Vest4
0.65
MutPred
0.68
Loss of stability (P = 0.0222);
MVP
0.89
MPC
0.63
ClinPred
0.87
D
GERP RS
4.2
Varity_R
0.094
gMVP
0.42

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: rs1262166840; hg19: chrX-107976525; API