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GeneBe

X-108733240-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001379150.1(IRS4):c.3105C>T(p.Ala1035=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,210,095 control chromosomes in the GnomAD database, including 26 homozygotes. There are 666 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 13 hom., 323 hem., cov: 23)
Exomes 𝑓: 0.0012 ( 13 hom. 343 hem. )

Consequence

IRS4
NM_001379150.1 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.706
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 Benign. Variant got -15 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=-0.67).
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-108733240-G-A is Benign according to our data. Variant chrX-108733240-G-A is described in ClinVar as [Benign]. Clinvar id is 716036.Status of the report is criteria_provided_single_submitter, 1 stars.
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=0.706 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1183/111863) while in subpopulation AFR AF= 0.0368 (1134/30789). AF 95% confidence interval is 0.0351. There are 13 homozygotes in gnomad4. There are 323 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRS4NM_001379150.1 linkuse as main transcriptc.3105C>T p.Ala1035= synonymous_variant 1/2 ENST00000372129.4
IRS4NM_003604.2 linkuse as main transcriptc.3105C>T p.Ala1035= synonymous_variant 1/1
IRS4XM_011531061.2 linkuse as main transcriptc.3105C>T p.Ala1035= synonymous_variant 1/3
IRS4XM_006724713.4 linkuse as main transcriptc.3105C>T p.Ala1035= synonymous_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRS4ENST00000372129.4 linkuse as main transcriptc.3105C>T p.Ala1035= synonymous_variant 1/2 NM_001379150.1 A2
IRS4ENST00000564206.2 linkuse as main transcriptc.3105C>T p.Ala1035= synonymous_variant 1/1 P5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0105
AC:
1177
AN:
111810
Hom.:
13
Cov.:
23
AF XY:
0.00945
AC XY:
321
AN XY:
33970
show subpopulations
Gnomad AFR
AF:
0.0367
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00349
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000373
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000565
Gnomad OTH
AF:
0.00532
GnomAD3 exomes
AF:
0.00312
AC:
572
AN:
183503
Hom.:
4
AF XY:
0.00230
AC XY:
156
AN XY:
67935
show subpopulations
Gnomad AFR exome
AF:
0.0377
Gnomad AMR exome
AF:
0.00204
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000524
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000134
Gnomad OTH exome
AF:
0.00177
GnomAD4 exome
AF:
0.00115
AC:
1268
AN:
1098232
Hom.:
13
Cov.:
32
AF XY:
0.000943
AC XY:
343
AN XY:
363588
show subpopulations
Gnomad4 AFR exome
AF:
0.0392
Gnomad4 AMR exome
AF:
0.00219
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000554
Gnomad4 FIN exome
AF:
0.0000247
Gnomad4 NFE exome
AF:
0.0000641
Gnomad4 OTH exome
AF:
0.00204
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0106
AC:
1183
AN:
111863
Hom.:
13
Cov.:
23
AF XY:
0.00949
AC XY:
323
AN XY:
34033
show subpopulations
Gnomad4 AFR
AF:
0.0368
Gnomad4 AMR
AF:
0.00348
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000375
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000565
Gnomad4 OTH
AF:
0.00525
Alfa
AF:
0.00491
Hom.:
24
Bravo
AF:
0.0123
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.67
Cadd
Benign
12
Dann
Benign
0.74

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: rs143866591; hg19: chrX-107976470; API