rs61729777

Variant names:

• chr18-47157482-T-C
• rs61729777
• NM_016097.5:c.147A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016097.5(IER3IP1):​c.147A>G​(p.Lys49Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,614,182 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: IER3IP1 NM_016097.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.97
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 18-47157482-T-C is Benign according to our data. Variant chr18-47157482-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.147A>G	p.Lys49Lys	synonymous	Exon 2 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.147A>G	p.Lys49Lys	synonymous	Exon 2 of 3	ENSP00000256433.3	Q9Y5U9
	ENSG00000267228	ENST00000588705.1	TSL:2	n.147A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000465194.1
	IER3IP1	ENST00000932440.1		c.264A>G	p.Lys88Lys	synonymous	Exon 3 of 4	ENSP00000602499.1

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 152234 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000477 AC: 120 AN: 251410 AF XY: 0.000294

Gnomad AFR exome AF: 0.00603

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461830 Hom.: 1 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727212

African (AFR) AF: 0.00576 AC: 193 AN: 33478

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.000298 AC: 18 AN: 60394

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152352 Hom.: 2 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74506

African (AFR) AF: 0.00628 AC: 261 AN: 41584

American (AMR) AF: 0.000784 AC: 12 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00220

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	IER3IP1-related disorder (1)
-	-	1	Microcephaly, epilepsy, and diabetes syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.5
DANN	Benign	0.55
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61729777; hg19: chr18-44683853;