Variant 5-5447734-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015325.3(ICE1):c.521A>T(p.Glu174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,583,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ICE1
NM_015325.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1447039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICE1	NM_015325.3 linkuse as main transcript	c.521A>T	p.Glu174Val	missense_variant	9/19	ENST00000296564.9	NP_056140.1	Q9Y2F5
ICE1	XM_011513999.3 linkuse as main transcript	c.521A>T	p.Glu174Val	missense_variant	9/17		XP_011512301.1
ICE1	XM_047417046.1 linkuse as main transcript	c.521A>T	p.Glu174Val	missense_variant	9/14		XP_047273002.1
ICE1	XM_047417047.1 linkuse as main transcript	c.521A>T	p.Glu174Val	missense_variant	9/15		XP_047273003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICE1	ENST00000296564.9 linkuse as main transcript	c.521A>T	p.Glu174Val	missense_variant	9/19	1	NM_015325.3	ENSP00000296564.7		Q9Y2F5
ICE1	ENST00000512608.5 linkuse as main transcript	c.290A>T	p.Glu97Val	missense_variant	9/11	4		ENSP00000485617.1		A0A096LPH9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000484

AC:

AN:

206652

Hom.:

AF XY:

0.00000904

AC XY:

AN XY:

110646

show subpopulations

Gnomad AFR exome

AF:

0.0000802

Gnomad AMR exome

AF:

0.00

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:

0.00000210

AC:

AN:

1431756

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000607

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2024

The c.521A>T (p.E174V) alteration is located in exon 9 (coding exon 9) of the ICE1 gene. This alteration results from a A to T substitution at nucleotide position 521, causing the glutamic acid (E) at amino acid position 174 to be replaced by a valine (V). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.47

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.4

.;D

REVEL

Benign

0.069

Sift

Benign

0.038

.;D

Sift4G

Pathogenic

0.0

D;T

Polyphen

1.0

.;D

Vest4

0.52

MutPred

0.19

.;Loss of helix (P = 0.0138);

MVP

0.043

MPC

0.51

ClinPred

0.79

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over