rs5498

chr19-10285007-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000201.3(ICAM1):c.1405A>G(p.Lys469Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,613,062 control chromosomes in the GnomAD database, including 148,506 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (11682 hom., cov: 32)
  • Exomes 𝑓: 0.43 (136824 hom.)
• Consequence: ICAM1 NM_000201.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.186

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]

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

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9145012E-4).
• BP6: Variant 19-10285007-A-G is Benign according to our data. Variant chr19-10285007-A-G is described in ClinVar as [Benign]. Clinvar id is 3060077.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-10285007-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICAM1	NM_000201.3	c.1405A>G	p.Lys469Glu	missense_variant	6/7	ENST00000264832.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICAM1	ENST00000264832.8	c.1405A>G	p.Lys469Glu	missense_variant	6/7	1	NM_000201.3	P1
LIMASI	ENST00000592893.1	n.102T>C		non_coding_transcript_exon_variant	1/3	3
ICAM1	ENST00000423829.2	c.739A>G	p.Lys247Glu	missense_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56534 AN: 151900 Hom.: 11683 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.438 AC: 109733 AN: 250628 Hom.: 25472 AF XY: 0.442 AC XY: 59930 AN XY: 135520

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.466

Gnomad EAS exome AF: 0.275

Gnomad SAS exome AF: 0.488

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.432

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.429 AC: 626242 AN: 1461044 Hom.: 136824 Cov.: 53 AF XY: 0.431 AC XY: 313016 AN XY: 726776

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.586

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.342

Gnomad4 SAS exome AF: 0.487

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.421

GnomAD4 genome AF: 0.372 AC: 56537 AN: 152018 Hom.: 11682 Cov.: 32 AF XY: 0.376 AC XY: 27951 AN XY: 74290

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.460

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.420

Alfa AF: 0.425 Hom.: 35039

Bravo AF: 0.369

TwinsUK AF: 0.412 AC: 1526

ALSPAC AF: 0.422 AC: 1628

ESP6500AA AF: 0.193 AC: 849

ESP6500EA AF: 0.431 AC: 3708

ExAC AF: 0.428 AC: 51923

Asia WGS AF: 0.402 AC: 1400 AN: 3478

EpiCase AF: 0.439

EpiControl AF: 0.442

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ICAM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.32
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.042	T;T
MetaRNN	Benign	0.00019	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.5	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.020
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.018
MPC		0.22
ClinPred		0.00058	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs5498; hg19: chr19-10395683; COSMIC: COSV53424462; COSMIC: COSV53424462;