chr5-5461120-A-G

Position:

• chr5-5461120-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015325.3(ICE1):​c.1786A>G​(p.Lys596Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,613,960 control chromosomes in the GnomAD database, including 1,945 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.063 (997 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (948 hom.)
• Consequence: ICE1 NM_015325.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.206

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038980544).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICE1	NM_015325.3	c.1786A>G	p.Lys596Glu	missense_variant	13/19	ENST00000296564.9	NP_056140.1
ICE1	XM_011513999.3	c.1786A>G	p.Lys596Glu	missense_variant	13/17		XP_011512301.1
ICE1	XM_047417046.1	c.1786A>G	p.Lys596Glu	missense_variant	13/14		XP_047273002.1
ICE1	XM_047417047.1	c.1786A>G	p.Lys596Glu	missense_variant	13/15		XP_047273003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICE1	ENST00000296564.9	c.1786A>G	p.Lys596Glu	missense_variant	13/19	1	NM_015325.3	ENSP00000296564	P1

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9606 AN: 152144 Hom.: 996 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0421

GnomAD3 exomes AF: 0.0157 AC: 3909 AN: 249014 Hom.: 392 AF XY: 0.0122 AC XY: 1644 AN XY: 135118

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.00886

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000541

Gnomad OTH exome AF: 0.00497

GnomAD4 exome AF: 0.00638 AC: 9326 AN: 1461698 Hom.: 948 Cov.: 39 AF XY: 0.00553 AC XY: 4018 AN XY: 727128

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000262

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0633 AC: 9634 AN: 152262 Hom.: 997 Cov.: 33 AF XY: 0.0604 AC XY: 4494 AN XY: 74450

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0127 Hom.: 263

Bravo AF: 0.0721

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.221 AC: 821

ESP6500EA AF: 0.000610 AC: 5

ExAC AF: 0.0195 AC: 2357

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000948

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.4
DANN	Benign	0.90
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.020
Sift	Benign	0.30	T
Sift4G	Benign	0.66	T
Polyphen		0.0090	B
Vest4		0.035
MPC		0.15
ClinPred		0.0018	T
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.080

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: rs10475299; hg19: chr5-5461233; COSMIC: COSV56825989;