chr18-47156119-A-G

Variant names:

• chr18-47156119-A-G
• rs150586939
• NM_016097.5:c.*58T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016097.5(IER3IP1):​c.*58T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,055,584 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (186 hom.)
• Consequence: IER3IP1 NM_016097.5 3_prime_UTR
• Scores: Splicing: ADA: 0.00003319
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 B:2
• Conservation: PhyloP100: 0.129

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]

ENSG00000267228 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IER3IP1	NM_016097.5	c.*58T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000256433.6	NP_057181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IER3IP1	ENST00000256433	c.*58T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_016097.5	ENSP00000256433.3
ENSG00000267228	ENST00000588705.1	n.*58T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 6	2		ENSP00000465194.1
ENSG00000267228	ENST00000588705.1	n.*58T>C		3_prime_UTR_variant	Exon 3 of 6	2		ENSP00000465194.1

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 798 AN: 152182 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00717

GnomAD4 exome AF: 0.00481 AC: 4347 AN: 903284 Hom.: 186 Cov.: 12 AF XY: 0.00455 AC XY: 2148 AN XY: 472322

Gnomad4 AFR exome AF: 0.00107

Gnomad4 AMR exome AF: 0.000211

Gnomad4 ASJ exome AF: 0.00346

Gnomad4 EAS exome AF: 0.0850

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.00473

Gnomad4 NFE exome AF: 0.000596

Gnomad4 OTH exome AF: 0.00828

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152300 Hom.: 27 Cov.: 32 AF XY: 0.00593 AC XY: 442 AN XY: 74482

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00547

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00191 Hom.: 1

Bravo AF: 0.00603

Asia WGS AF: 0.0460 AC: 160 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

Self-limited epilepsy with centrotemporal spikes Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15 -

IER3IP1-related disorder Benign:1

May 24, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epilepsy Benign:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

NM_016097.4:c.*58T>C in the IER3IP1 gene has an allele frequency of 0.008 in the gnomAD database, including 12 homozygous occurrences. The allele frequency is 0.1321 in the Asian subpopulation (total allele is less than 2000). Benign computational verdict because benign prediction from DANN. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS2; BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.4
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs150586939; hg19: chr18-44682490;