18-47156187-A-C

Position:

• chr18-47156187-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016097.5(IER3IP1):​c.239T>G​(p.Leu80Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L80L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IER3IP1 NM_016097.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

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]

ACMG classification

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.239T>G	p.Leu80Ter	stop_gained	3/3	ENST00000256433.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IER3IP1	ENST00000256433.6	c.239T>G	p.Leu80Ter	stop_gained	3/3	1	NM_016097.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly, epilepsy, and diabetes syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 26, 2019

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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with IER3IP1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the IER3IP1 gene (p.Leu80*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acids of the IER3IP1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D
Vest4		0.19
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs1599991332; hg19: chr18-44682558;