9-129177305-A-C

Position:

• chr9-129177305-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_203434.3(IER5L):​c.748T>G​(p.Cys250Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000318 in 1,259,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: IER5L NM_203434.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29

Genes affected

IER5L (HGNC:23679): (immediate early response 5 like)

ENSG00000235007 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IER5L	NM_203434.3	c.748T>G	p.Cys250Gly	missense_variant	1/1	ENST00000372491.4	NP_982258.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IER5L	ENST00000372491.4	c.748T>G	p.Cys250Gly	missense_variant	1/1	6	NM_203434.3	ENSP00000361569.2
ENSG00000235007	ENST00000674648.1	c.109-31564A>C		intron_variant				ENSP00000502744.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000237 AC: 3 AN: 126532 Hom.: 0 AF XY: 0.0000139 AC XY: 1 AN XY: 72060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000318 AC: 4 AN: 1259840 Hom.: 0 Cov.: 31 AF XY: 0.00000322 AC XY: 2 AN XY: 620980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.748T>G (p.C250G) alteration is located in exon 1 (coding exon 1) of the IER5L gene. This alteration results from a T to G substitution at nucleotide position 748, causing the cysteine (C) at amino acid position 250 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.088	T
Sift4G	Benign	0.57	T
Polyphen		0.99	D
Vest4		0.48
MutPred		0.79		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.043
MPC		1.1
ClinPred		0.59	D
GERP RS		2.9
Varity_R		0.24
gMVP		0.31

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: rs765030656; hg19: chr9-131939584;