rs5498

Positions:

• chr19-10285007-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
ICAM1	NM_000201.3	c.1405A>G	p.Lys469Glu	missense_variant	6/7	ENST00000264832.8	NP_000192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICAM1	ENST00000264832.8	c.1405A>G	p.Lys469Glu	missense_variant	6/7	1	NM_000201.3	ENSP00000264832	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		ENSP00000413124

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: no assertion criteria provided

Submissions by phenotype

ICAM1-related disorder Benign:1

Benign, no assertion criteria provided

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;