chrX-108733631-G-A
Position:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001379150.1(IRS4):c.2714C>T(p.Pro905Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,210,012 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )
Consequence
IRS4
NM_001379150.1 missense
NM_001379150.1 missense
Scores
17
Clinical Significance
Conservation
PhyloP100: 3.70
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 -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.041858345).
BS2
High Hemizygotes in GnomAdExome4 at 4 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IRS4 | NM_001379150.1 | c.2714C>T | p.Pro905Leu | missense_variant | 1/2 | ENST00000372129.4 | |
IRS4 | NM_003604.2 | c.2714C>T | p.Pro905Leu | missense_variant | 1/1 | ||
IRS4 | XM_011531061.2 | c.2714C>T | p.Pro905Leu | missense_variant | 1/3 | ||
IRS4 | XM_006724713.4 | c.2714C>T | p.Pro905Leu | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IRS4 | ENST00000372129.4 | c.2714C>T | p.Pro905Leu | missense_variant | 1/2 | NM_001379150.1 | A2 | ||
IRS4 | ENST00000564206.2 | c.2714C>T | p.Pro905Leu | missense_variant | 1/1 | P5 |
Frequencies
GnomAD3 genomes AF: 0.00000895 AC: 1AN: 111767Hom.: 0 Cov.: 22 AF XY: 0.0000295 AC XY: 1AN XY: 33939
GnomAD3 genomes
AF:
AC:
1
AN:
111767
Hom.:
Cov.:
22
AF XY:
AC XY:
1
AN XY:
33939
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000218 AC: 4AN: 183516Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67944
GnomAD3 exomes
AF:
AC:
4
AN:
183516
Hom.:
AF XY:
AC XY:
0
AN XY:
67944
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000109 AC: 12AN: 1098245Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 4AN XY: 363599
GnomAD4 exome
AF:
AC:
12
AN:
1098245
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
363599
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000895 AC: 1AN: 111767Hom.: 0 Cov.: 22 AF XY: 0.0000295 AC XY: 1AN XY: 33939
GnomAD4 genome
AF:
AC:
1
AN:
111767
Hom.:
Cov.:
22
AF XY:
AC XY:
1
AN XY:
33939
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
AF:
AC:
2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | The c.2714C>T (p.P905L) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a C to T substitution at nucleotide position 2714, causing the proline (P) at amino acid position 905 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of MoRF binding (P = 0.0377);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at