19-10285120-C-T

Position:

chr19-10285120-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000201.3(ICAM1):c.1432C>T(p.Arg478Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,614,078 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R478Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 18 hom. )

Consequence

ICAM1
NM_000201.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.747

Variant links:

Genes affected

ICAM1 (HGNC:5344): (intercellular adhesion molecule 1) This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by Rhinovirus as a receptor. [provided by RefSeq, Jul 2008]

ICAM1 links:

LIMASI (HGNC:56357): (lncRNA inflammatory and mucous response associated, antisense to ICAM1)

LIMASI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006729126).

BS2

High Homozygotes in GnomAdExome4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICAM1	NM_000201.3 linkuse as main transcript	c.1432C>T	p.Arg478Trp	missense_variant	7/7	ENST00000264832.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ICAM1	ENST00000264832.8 linkuse as main transcript	c.1432C>T	p.Arg478Trp	missense_variant	7/7	1	NM_000201.3	P1
ICAM1	ENST00000423829.2 linkuse as main transcript	c.766C>T	p.Arg256Trp	missense_variant	5/5	2
LIMASI	ENST00000592893.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00390

AC:

593

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00592

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00377

AC:

947

AN:

251132

Hom.:

AF XY:

0.00393

AC XY:

533

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.00620

Gnomad NFE exome

AF:

0.00530

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00510

AC:

7454

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00500

AC XY:

3637

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00306

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00209

Gnomad4 FIN exome

AF:

0.00580

Gnomad4 NFE exome

AF:

0.00589

Gnomad4 OTH exome

AF:

0.00363

GnomAD4 genome

AF:

0.00389

AC:

593

AN:

152296

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

284

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00584

Gnomad4 NFE

AF:

0.00592

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00446

Hom.:

Bravo

AF:

0.00373

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00410

AC:

498

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00545

EpiControl

AF:

0.00492

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Malaria, susceptibility to

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

ICAM1 NM_000201.2 exon 7 p.Arg478Trp (c.1432C>T): This variant has not been reported in the literature in humans, but is present in 0.5% (148/25102) of Finnish alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-10395796-C-T). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant will not impact the protein (Vischer 2006 PMID:188205950). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.0097

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.036

Sift

Benign

0.19

T;T

Sift4G

Benign

0.065

T;T

Polyphen

0.99

D;D

Vest4

0.19

MVP

0.51

MPC

0.60

ClinPred

0.037

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.48

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