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rs80131334

chrX-108735112-T-AchrX-108735112-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001379150.1(IRS4):c.1233A>T(p.Arg411=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,209,450 control chromosomes in the GnomAD database, including 1,525 homozygotes. There are 22,775 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 0.055 ( 149 hom., 1680 hem., cov: 22)
Exomes 𝑓: 0.059 ( 1376 hom. 21095 hem. )

Consequence

IRS4
NM_001379150.1 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.435
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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=-0.85).
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-108735112-T-A is Benign according to our data. Variant chrX-108735112-T-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=0.435 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 = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRS4NM_001379150.1 linkuse as main transcriptc.1233A>T p.Arg411= synonymous_variant 1/2 ENST00000372129.4
IRS4NM_003604.2 linkuse as main transcriptc.1233A>T p.Arg411= synonymous_variant 1/1
IRS4XM_011531061.2 linkuse as main transcriptc.1233A>T p.Arg411= synonymous_variant 1/3
IRS4XM_006724713.4 linkuse as main transcriptc.1233A>T p.Arg411= synonymous_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRS4ENST00000372129.4 linkuse as main transcriptc.1233A>T p.Arg411= synonymous_variant 1/2 NM_001379150.1 A2
IRS4ENST00000564206.2 linkuse as main transcriptc.1233A>T p.Arg411= synonymous_variant 1/1 P5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0551
AC:
6135
AN:
111404
Hom.:
148
Cov.:
22
AF XY:
0.0498
AC XY:
1674
AN XY:
33620
show subpopulations
Gnomad AFR
AF:
0.0507
Gnomad AMI
AF:
0.0162
Gnomad AMR
AF:
0.0765
Gnomad ASJ
AF:
0.0409
Gnomad EAS
AF:
0.00113
Gnomad SAS
AF:
0.0569
Gnomad FIN
AF:
0.0362
Gnomad MID
AF:
0.0638
Gnomad NFE
AF:
0.0598
Gnomad OTH
AF:
0.0676
GnomAD3 exomes
AF:
0.0540
AC:
9871
AN:
182632
Hom.:
214
AF XY:
0.0515
AC XY:
3463
AN XY:
67272
show subpopulations
Gnomad AFR exome
AF:
0.0545
Gnomad AMR exome
AF:
0.0838
Gnomad ASJ exome
AF:
0.0429
Gnomad EAS exome
AF:
0.000505
Gnomad SAS exome
AF:
0.0594
Gnomad FIN exome
AF:
0.0304
Gnomad NFE exome
AF:
0.0576
Gnomad OTH exome
AF:
0.0522
GnomAD4 exome
AF:
0.0589
AC:
64701
AN:
1097991
Hom.:
1376
Cov.:
34
AF XY:
0.0581
AC XY:
21095
AN XY:
363383
show subpopulations
Gnomad4 AFR exome
AF:
0.0512
Gnomad4 AMR exome
AF:
0.0815
Gnomad4 ASJ exome
AF:
0.0406
Gnomad4 EAS exome
AF:
0.000199
Gnomad4 SAS exome
AF:
0.0583
Gnomad4 FIN exome
AF:
0.0325
Gnomad4 NFE exome
AF:
0.0623
Gnomad4 OTH exome
AF:
0.0556
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0551
AC:
6144
AN:
111459
Hom.:
149
Cov.:
22
AF XY:
0.0499
AC XY:
1680
AN XY:
33685
show subpopulations
Gnomad4 AFR
AF:
0.0507
Gnomad4 AMR
AF:
0.0767
Gnomad4 ASJ
AF:
0.0409
Gnomad4 EAS
AF:
0.00114
Gnomad4 SAS
AF:
0.0578
Gnomad4 FIN
AF:
0.0362
Gnomad4 NFE
AF:
0.0598
Gnomad4 OTH
AF:
0.0668
Alfa
AF:
0.0300
Hom.:
220
Bravo
AF:
0.0575
EpiCase
AF:
0.0608
EpiControl
AF:
0.0590

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
Cadd
Benign
5.1
Dann
Benign
0.80

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: rs80131334; hg19: chrX-107978342; COSMIC: COSV64535286; COSMIC: COSV64535286; API