chr18-47176216-A-C

Variant names:

• chr18-47176216-A-C
• rs387907011
• NM_016097.5:c.62T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_016097.5(IER3IP1):​c.62T>G​(p.Val21Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V21V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IER3IP1 NM_016097.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 6.17

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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.39197 (below the threshold of 3.09). Trascript score misZ: -0.049149 (below the threshold of 3.09). GenCC associations: The gene is linked to primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, microcephaly, epilepsy, and diabetes syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IER3IP1	NM_016097.5	c.62T>G	p.Val21Gly	missense_variant	Exon 1 of 3	ENST00000256433.6	NP_057181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IER3IP1	ENST00000256433.6	c.62T>G	p.Val21Gly	missense_variant	Exon 1 of 3	1	NM_016097.5	ENSP00000256433.3
ENSG00000267228	ENST00000588705.1	n.62T>G		non_coding_transcript_exon_variant	Exon 1 of 6	2		ENSP00000465194.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000212 AC: 5 AN: 235702 AF XY: 0.0000156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000149

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: 0.00000275 AC: 4 AN: 1454620 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722956

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33382

Gnomad4 AMR exome AF: 0.0000681 AC: 3 AN: 44048

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25936

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39510

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 84888

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52232

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1109036

Gnomad4 Remaining exome AF: 0.0000167 AC: 1 AN: 60040

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, epilepsy, and diabetes syndrome 1 Pathogenic:1

May 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

May 26, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in compound heterozygous state in a patient with microcephaly, epilepsy, and neonatal diabetes; however, the variant in trans is of uncertain significance (Shalev et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28915629, 28711742, 31589614, 34229114, 21835305, 24138066) -

Microcephaly, epilepsy, and diabetes syndrome Uncertain:1

Aug 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with glycine at codon 21 of the IER3IP1 protein (p.Val21Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs387907011, ExAC 0.04%). This missense change has been observed in individuals with microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome (PMID: 21835305, 24138066). ClinVar contains an entry for this variant (Variation ID: 30785). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.25	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.6	D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.95	P;.
Vest4		0.87
MutPred		0.75		Loss of stability (P = 0.0093);Loss of stability (P = 0.0093);
MVP		0.84
MPC		0.30
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.96
Mutation Taster		=26/74	disease causing

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: rs387907011; hg19: chr18-44702587;