X-108732657-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001379150.1(IRS4):​c.3688G>A​(p.Asp1230Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,240 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1230Y) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

1
3
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.830
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13055342).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRS4NM_001379150.1 linkc.3688G>A p.Asp1230Asn missense_variant Exon 1 of 2 ENST00000372129.4 NP_001366079.1
IRS4NM_003604.2 linkc.3688G>A p.Asp1230Asn missense_variant Exon 1 of 1 NP_003595.1 O14654
IRS4XM_011531061.2 linkc.3688G>A p.Asp1230Asn missense_variant Exon 1 of 3 XP_011529363.1
IRS4XM_006724713.4 linkc.3688G>A p.Asp1230Asn 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.3688G>A p.Asp1230Asn missense_variant Exon 1 of 2 6 NM_001379150.1 ENSP00000361202.3 A0A804CF45
IRS4ENST00000564206.2 linkc.3688G>A p.Asp1230Asn missense_variant Exon 1 of 1 6 ENSP00000505547.1 O14654

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1098240
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
363596
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.0000217
GnomAD4 genome
Cov.:
23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
.;T
FATHMM_MKL
Benign
0.34
N
LIST_S2
Benign
0.56
T;T
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
.;L
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.0
D;N
REVEL
Benign
0.12
Sift
Benign
0.61
T;T
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.74
.;P
Vest4
0.093
MutPred
0.071
.;Gain of relative solvent accessibility (P = 0.0479);
MVP
0.35
MPC
0.48
ClinPred
0.97
D
GERP RS
3.5
Varity_R
0.089
gMVP
0.071

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: rs28546943; hg19: chrX-107975887; API