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GeneBe

rs73253702

chrX-108736207-G-AchrX-108736207-G-CchrX-108736207-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_001379150.1(IRS4):c.138C>T(p.Thr46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,208,224 control chromosomes in the GnomAD database, including 1,589 homozygotes. There are 23,214 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

Frequency

Genomes: 𝑓 0.062 ( 182 hom., 1892 hem., cov: 21)
Exomes 𝑓: 0.060 ( 1407 hom. 21322 hem. )

Consequence

IRS4
NM_001379150.1 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52
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]
IRS4-AS1 (HGNC:55650): (IRS4 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant X-108736207-G-A is Benign according to our data. Variant chrX-108736207-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.52 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRS4NM_001379150.1 linkuse as main transcriptc.138C>T p.Thr46= synonymous_variant 1/2 ENST00000372129.4
IRS4NM_003604.2 linkuse as main transcriptc.138C>T p.Thr46= synonymous_variant 1/1
IRS4XM_011531061.2 linkuse as main transcriptc.138C>T p.Thr46= synonymous_variant 1/3
IRS4XM_006724713.4 linkuse as main transcriptc.138C>T p.Thr46= synonymous_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRS4ENST00000372129.4 linkuse as main transcriptc.138C>T p.Thr46= synonymous_variant 1/2 NM_001379150.1 A2
IRS4-AS1ENST00000668534.1 linkuse as main transcriptn.117G>A non_coding_transcript_exon_variant 1/3
IRS4ENST00000564206.2 linkuse as main transcriptc.138C>T p.Thr46= synonymous_variant 1/1 P5
IRS4-AS1ENST00000608811.1 linkuse as main transcriptn.197G>A non_coding_transcript_exon_variant 1/24

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0616
AC:
6833
AN:
110991
Hom.:
181
Cov.:
21
AF XY:
0.0566
AC XY:
1881
AN XY:
33253
show subpopulations
Gnomad AFR
AF:
0.0720
Gnomad AMI
AF:
0.0149
Gnomad AMR
AF:
0.0784
Gnomad ASJ
AF:
0.0432
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.0569
Gnomad FIN
AF:
0.0365
Gnomad MID
AF:
0.0601
Gnomad NFE
AF:
0.0605
Gnomad OTH
AF:
0.0699
GnomAD3 exomes
AF:
0.0562
AC:
10106
AN:
179974
Hom.:
225
AF XY:
0.0536
AC XY:
3575
AN XY:
66656
show subpopulations
Gnomad AFR exome
AF:
0.0754
Gnomad AMR exome
AF:
0.0860
Gnomad ASJ exome
AF:
0.0446
Gnomad EAS exome
AF:
0.000510
Gnomad SAS exome
AF:
0.0595
Gnomad FIN exome
AF:
0.0305
Gnomad NFE exome
AF:
0.0581
Gnomad OTH exome
AF:
0.0535
GnomAD4 exome
AF:
0.0597
AC:
65480
AN:
1097184
Hom.:
1407
Cov.:
33
AF XY:
0.0587
AC XY:
21322
AN XY:
363058
show subpopulations
Gnomad4 AFR exome
AF:
0.0735
Gnomad4 AMR exome
AF:
0.0831
Gnomad4 ASJ exome
AF:
0.0424
Gnomad4 EAS exome
AF:
0.000199
Gnomad4 SAS exome
AF:
0.0584
Gnomad4 FIN exome
AF:
0.0325
Gnomad4 NFE exome
AF:
0.0623
Gnomad4 OTH exome
AF:
0.0574
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0617
AC:
6847
AN:
111040
Hom.:
182
Cov.:
21
AF XY:
0.0568
AC XY:
1892
AN XY:
33312
show subpopulations
Gnomad4 AFR
AF:
0.0721
Gnomad4 AMR
AF:
0.0787
Gnomad4 ASJ
AF:
0.0432
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.0578
Gnomad4 FIN
AF:
0.0365
Gnomad4 NFE
AF:
0.0604
Gnomad4 OTH
AF:
0.0690
Alfa
AF:
0.0369
Hom.:
241
Bravo
AF:
0.0645
EpiCase
AF:
0.0609
EpiControl
AF:
0.0608

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
Cadd
Benign
19
Dann
Benign
0.93

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: rs73253702; hg19: chrX-107979437; COSMIC: COSV64536282; COSMIC: COSV64536282; API