rs536988795
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016097.5(IER3IP1):āc.223A>Gā(p.Ile75Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000216 in 1,571,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00011 ( 0 hom., cov: 33)
Exomes š: 0.000013 ( 0 hom. )
Consequence
IER3IP1
NM_016097.5 missense
NM_016097.5 missense
Scores
4
9
5
Clinical Significance
Conservation
PhyloP100: 6.20
Genes affected
IER3IP1 (HGNC:18550): (immediate early response 3 interacting protein 1) This gene encodes a small protein that is localized to the endoplasmic reticulum (ER) and may play a role in the ER stress response by mediating cell differentiation and apoptosis. Transcription of this gene is regulated by tumor necrosis factor alpha and specificity protein 1 (Sp1). Mutations in this gene may play a role in microcephaly, epilepsy, and diabetes syndrome (MEDS), and a pseudogene of this gene is located on the long arm of chromosome 12. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IER3IP1 | NM_016097.5 | c.223A>G | p.Ile75Val | missense_variant | 3/3 | ENST00000256433.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IER3IP1 | ENST00000256433.6 | c.223A>G | p.Ile75Val | missense_variant | 3/3 | 1 | NM_016097.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 151744Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250038Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135098
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GnomAD4 exome AF: 0.0000127 AC: 18AN: 1419602Hom.: 0 Cov.: 26 AF XY: 0.0000113 AC XY: 8AN XY: 708384
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 151860Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74218
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly, epilepsy, and diabetes syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 09, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the IER3IP1 protein (p.Ile75Val). This variant is present in population databases (rs536988795, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with IER3IP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 472569). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at L80 (P = 0.0233);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at