chr18-47156242-G-GA

Variant names:

• chr18-47156242-G-GA
• rs553378864
• NM_016097.5:c.194-11dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_016097.5(IER3IP1):​c.194-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,230,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IER3IP1 NM_016097.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.679
• Publications: 0 publications found

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]

IER3IP1 Gene-Disease associations (from GenCC):

• microcephaly, epilepsy, and diabetes syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• primary microcephaly-epilepsy-permanent neonatal diabetes syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ENSG00000267228 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the NFE (0.00394) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).
• BP6: Variant 18-47156242-G-GA is Benign according to our data. Variant chr18-47156242-G-GA is described in ClinVar as Benign. ClinVar VariationId is 2897614.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016097.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IER3IP1	NM_016097.5	MANE Select	c.194-11dupT		intron	N/A	NP_057181.1	Q9Y5U9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IER3IP1	ENST00000256433.6	TSL:1 MANE Select	c.194-11_194-10insT		intron	N/A	ENSP00000256433.3	Q9Y5U9
	ENSG00000267228	ENST00000588705.1	TSL:2	n.194-11_194-10insT		intron	N/A	ENSP00000465194.1
	IER3IP1	ENST00000932440.1		c.311-11_311-10insT		intron	N/A	ENSP00000602499.1

Frequencies

GnomAD3 genomes AF: 0.0000559 AC: 8 AN: 143214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000769

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00184 AC: 308 AN: 167278 AF XY: 0.00143

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00142

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00373

GnomAD4 exome AF: 0.00372 AC: 4575 AN: 1230330 Hom.: 0 Cov.: 22 AF XY: 0.00347 AC XY: 2137 AN XY: 615150

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00399 AC: 107 AN: 26838

American (AMR) AF: 0.00327 AC: 110 AN: 33636

Ashkenazi Jewish (ASJ) AF: 0.00261 AC: 58 AN: 22194

East Asian (EAS) AF: 0.00129 AC: 45 AN: 34918

South Asian (SAS) AF: 0.00274 AC: 189 AN: 68896

European-Finnish (FIN) AF: 0.00157 AC: 76 AN: 48370

Middle Eastern (MID) AF: 0.00196 AC: 10 AN: 5110

European-Non Finnish (NFE) AF: 0.00405 AC: 3805 AN: 939322

Other (OTH) AF: 0.00343 AC: 175 AN: 51046

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000559 AC: 8 AN: 143214 Hom.: 0 Cov.: 32 AF XY: 0.0000432 AC XY: 3 AN XY: 69426

African (AFR) AF: 0.0000257 AC: 1 AN: 38876

American (AMR) AF: 0.00 AC: 0 AN: 14440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 4966

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4536

European-Finnish (FIN) AF: 0.000112 AC: 1 AN: 8912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000769 AC: 5 AN: 65018

Other (OTH) AF: 0.00 AC: 0 AN: 1964

Alfa AF: 0.00589 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Microcephaly, epilepsy, and diabetes syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs553378864; hg19: chr18-44682613;