X-108732921-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001379150.1(IRS4):​c.3424G>T​(p.Ala1142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,066,495 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

1
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29924816).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRS4NM_001379150.1 linkc.3424G>T p.Ala1142Ser missense_variant Exon 1 of 2 ENST00000372129.4 NP_001366079.1
IRS4NM_003604.2 linkc.3424G>T p.Ala1142Ser missense_variant Exon 1 of 1 NP_003595.1 O14654
IRS4XM_011531061.2 linkc.3424G>T p.Ala1142Ser missense_variant Exon 1 of 3 XP_011529363.1
IRS4XM_006724713.4 linkc.3424G>T p.Ala1142Ser missense_variant Exon 1 of 2 XP_006724776.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRS4ENST00000372129.4 linkc.3424G>T p.Ala1142Ser missense_variant Exon 1 of 2 6 NM_001379150.1 ENSP00000361202.3 A0A804CF45
IRS4ENST00000564206.2 linkc.3424G>T p.Ala1142Ser missense_variant Exon 1 of 1 6 ENSP00000505547.1 O14654

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
0.00000188
AC:
2
AN:
1066495
Hom.:
0
Cov.:
31
AF XY:
0.00000291
AC XY:
1
AN XY:
343093
show subpopulations
Gnomad4 AFR exome
AF:
0.0000787
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 25, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3424G>T (p.A1142S) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a G to T substitution at nucleotide position 3424, causing the alanine (A) at amino acid position 1142 to be replaced by a serine (S). 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
0.16
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.38
T
M_CAP
Pathogenic
0.73
D
MetaRNN
Benign
0.30
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
0.19
N
REVEL
Benign
0.077
Sift
Uncertain
0.015
D
Sift4G
Uncertain
0.0040
D
Polyphen
0.85
P
Vest4
0.24
MutPred
0.15
Gain of glycosylation at A1142 (P = 0.0012);
MVP
0.27
MPC
0.45
ClinPred
0.55
D
GERP RS
5.3
Varity_R
0.14
gMVP
0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107976151; API