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GeneBe

rs2073114

chrX-108736282-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_001379150.1(IRS4):c.63G>A(p.Ala21=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,202,303 control chromosomes in the GnomAD database, including 39,372 homozygotes. There are 102,411 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.38 ( 7404 hom., 11748 hem., cov: 22)
Exomes 𝑓: 0.26 ( 31968 hom. 90663 hem. )

Consequence

IRS4
NM_001379150.1 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.671
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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=-0.46).
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-108736282-C-T is Benign according to our data. Variant chrX-108736282-C-T is described in ClinVar as [Benign]. Clinvar id is 1300045.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108736282-C-T 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=-0.671 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRS4NM_001379150.1 linkuse as main transcriptc.63G>A p.Ala21= synonymous_variant 1/2 ENST00000372129.4
IRS4NM_003604.2 linkuse as main transcriptc.63G>A p.Ala21= synonymous_variant 1/1
IRS4XM_011531061.2 linkuse as main transcriptc.63G>A p.Ala21= synonymous_variant 1/3
IRS4XM_006724713.4 linkuse as main transcriptc.63G>A p.Ala21= synonymous_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRS4ENST00000372129.4 linkuse as main transcriptc.63G>A p.Ala21= synonymous_variant 1/2 NM_001379150.1 A2
IRS4-AS1ENST00000668534.1 linkuse as main transcriptn.192C>T non_coding_transcript_exon_variant 1/3
IRS4ENST00000564206.2 linkuse as main transcriptc.63G>A p.Ala21= synonymous_variant 1/1 P5
IRS4-AS1ENST00000608811.1 linkuse as main transcriptn.272C>T non_coding_transcript_exon_variant 1/24

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.377
AC:
41439
AN:
109883
Hom.:
7401
Cov.:
22
AF XY:
0.362
AC XY:
11696
AN XY:
32313
show subpopulations
Gnomad AFR
AF:
0.656
Gnomad AMI
AF:
0.316
Gnomad AMR
AF:
0.515
Gnomad ASJ
AF:
0.181
Gnomad EAS
AF:
0.662
Gnomad SAS
AF:
0.417
Gnomad FIN
AF:
0.137
Gnomad MID
AF:
0.162
Gnomad NFE
AF:
0.210
Gnomad OTH
AF:
0.360
GnomAD3 exomes
AF:
0.346
AC:
61225
AN:
176758
Hom.:
10409
AF XY:
0.304
AC XY:
19262
AN XY:
63364
show subpopulations
Gnomad AFR exome
AF:
0.653
Gnomad AMR exome
AF:
0.641
Gnomad ASJ exome
AF:
0.181
Gnomad EAS exome
AF:
0.642
Gnomad SAS exome
AF:
0.419
Gnomad FIN exome
AF:
0.137
Gnomad NFE exome
AF:
0.194
Gnomad OTH exome
AF:
0.283
GnomAD4 exome
AF:
0.258
AC:
282352
AN:
1092370
Hom.:
31968
Cov.:
34
AF XY:
0.253
AC XY:
90663
AN XY:
358512
show subpopulations
Gnomad4 AFR exome
AF:
0.657
Gnomad4 AMR exome
AF:
0.632
Gnomad4 ASJ exome
AF:
0.187
Gnomad4 EAS exome
AF:
0.686
Gnomad4 SAS exome
AF:
0.418
Gnomad4 FIN exome
AF:
0.150
Gnomad4 NFE exome
AF:
0.210
Gnomad4 OTH exome
AF:
0.292
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.377
AC:
41499
AN:
109933
Hom.:
7404
Cov.:
22
AF XY:
0.363
AC XY:
11748
AN XY:
32373
show subpopulations
Gnomad4 AFR
AF:
0.656
Gnomad4 AMR
AF:
0.515
Gnomad4 ASJ
AF:
0.181
Gnomad4 EAS
AF:
0.662
Gnomad4 SAS
AF:
0.418
Gnomad4 FIN
AF:
0.137
Gnomad4 NFE
AF:
0.210
Gnomad4 OTH
AF:
0.358
Alfa
AF:
0.273
Hom.:
2622
Bravo
AF:
0.422
EpiCase
AF:
0.209
EpiControl
AF:
0.200

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 9 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 19, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
Cadd
Benign
7.0
Dann
Benign
0.95

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: rs2073114; hg19: chrX-107979512; COSMIC: COSV64534695; COSMIC: COSV64534695; API