5-5454585-T-C

Position:

• chr5-5454585-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015325.3(ICE1):​c.638T>C​(p.Leu213Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICE1 NM_015325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

ICE1 (HGNC:29154): (interactor of little elongation complex ELL subunit 1) Enables protein-macromolecule adaptor activity. Involved in several processes, including positive regulation of intracellular protein transport; positive regulation of transcription by RNA polymerase III; and snRNA transcription. Located in Cajal body; histone locus body; and transcriptionally active chromatin. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4175175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICE1	NM_015325.3	c.638T>C	p.Leu213Pro	missense_variant	11/19	ENST00000296564.9	NP_056140.1
ICE1	XM_011513999.3	c.638T>C	p.Leu213Pro	missense_variant	11/17		XP_011512301.1
ICE1	XM_047417046.1	c.638T>C	p.Leu213Pro	missense_variant	11/14		XP_047273002.1
ICE1	XM_047417047.1	c.638T>C	p.Leu213Pro	missense_variant	11/15		XP_047273003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICE1	ENST00000296564.9	c.638T>C	p.Leu213Pro	missense_variant	11/19	1	NM_015325.3	ENSP00000296564.7
ICE1	ENST00000512608.5	c.407T>C	p.Leu136Pro	missense_variant	11/11	4		ENSP00000485617.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461316 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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

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

May 30, 2023

The c.638T>C (p.L213P) alteration is located in exon 11 (coding exon 11) of the ICE1 gene. This alteration results from a T to C substitution at nucleotide position 638, causing the leucine (L) at amino acid position 213 to be replaced by a proline (P). 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	0.98
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.84
MutPred		0.61		.;Gain of catalytic residue at L213 (P = 0.023);
MVP		0.49
MPC		0.60
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.49

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-5454698;