5-5436472-A-G

Position:

• chr5-5436472-A-G

Variant summary

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

The NM_015325.3(ICE1):​c.139A>G​(p.Thr47Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000152 in 1,316,764 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: 0.0000015 (0 hom.)
• Consequence: ICE1 NM_015325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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]

ICE1 (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
ICE1	NM_015325.3	c.139A>G	p.Thr47Ala	missense_variant	2/19	ENST00000296564.9	NP_056140.1
ICE1	XM_011513999.3	c.139A>G	p.Thr47Ala	missense_variant	2/17		XP_011512301.1
ICE1	XM_047417046.1	c.139A>G	p.Thr47Ala	missense_variant	2/14		XP_047273002.1
ICE1	XM_047417047.1	c.139A>G	p.Thr47Ala	missense_variant	2/15		XP_047273003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICE1	ENST00000296564.9	c.139A>G	p.Thr47Ala	missense_variant	2/19	1	NM_015325.3	ENSP00000296564.7
ICE1	ENST00000512608	c.-93A>G		5_prime_UTR_premature_start_codon_gain_variant	2/11	4		ENSP00000485617.1
ICE1	ENST00000512608	c.-93A>G		5_prime_UTR_variant	2/11	4		ENSP00000485617.1
ICE1	ENST00000505464.1	n.313A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1316764 Hom.: 0 Cov.: 21 AF XY: 0.00000153 AC XY: 1 AN XY: 653798

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: 0.00000194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 20, 2021

The c.139A>G (p.T47A) alteration is located in exon 2 (coding exon 2) of the ICE1 gene. This alteration results from a A to G substitution at nucleotide position 139, causing the threonine (T) at amino acid position 47 to be replaced by an alanine (A). 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	0.84
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.15
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.25		Loss of methylation at K43 (P = 0.0495);
MVP		0.25
MPC		0.47
ClinPred		0.93	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.45

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: rs914476956; hg19: chr5-5436585;