18-47156183-A-G

Variant names:

• chr18-47156183-A-G
• rs768458884
• NM_016097.5:c.243T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_016097.5(IER3IP1):​c.243T>C​(p.Phe81Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,385,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IER3IP1 NM_016097.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 18-47156183-A-G is Benign according to our data. Variant chr18-47156183-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3640740.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.

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.243T>C	p.Phe81Phe	synonymous	Exon 3 of 3	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.243T>C	p.Phe81Phe	synonymous	Exon 3 of 3	ENSP00000256433.3	Q9Y5U9
	ENSG00000267228	ENST00000588705.1	TSL:2	n.243T>C		non_coding_transcript_exon	Exon 3 of 6	ENSP00000465194.1
	IER3IP1	ENST00000932440.1		c.360T>C	p.Phe120Phe	synonymous	Exon 4 of 4	ENSP00000602499.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250422 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385658 Hom.: 0 Cov.: 25 AF XY: 0.00000288 AC XY: 2 AN XY: 693404

African (AFR) AF: 0.00 AC: 0 AN: 31932

American (AMR) AF: 0.0000224 AC: 1 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39224

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1042816

Other (OTH) AF: 0.00 AC: 0 AN: 57928

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.5
DANN	Benign	0.70
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs768458884; hg19: chr18-44682554;