rs1799969

chr19-10284116-G-A

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.721G>A(p.Gly241Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,914 control chromosomes in the GnomAD database, including 10,768 homozygotes. In-silico tool predicts 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 0.091 (943 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9825 hom.)
• Consequence: ICAM1 NM_000201.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.71

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=8.133352E-4).
• BP6: Variant 19-10284116-G-A is Benign according to our data. Variant chr19-10284116-G-A is described in ClinVar as [Benign]. Clinvar id is 3060438.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICAM1	NM_000201.3	c.721G>A	p.Gly241Arg	missense_variant	4/7	ENST00000264832.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICAM1	ENST00000264832.8	c.721G>A	p.Gly241Arg	missense_variant	4/7	1	NM_000201.3	P1
LIMASI	ENST00000592893.1	n.141+852C>T		intron_variant, non_coding_transcript_variant		3
ICAM1	ENST00000423829.2	c.68-13G>A		splice_polypyrimidine_tract_variant, intron_variant		2
ICAM1	ENST00000592686.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13842 AN: 152000 Hom.: 942 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0724

GnomAD3 exomes AF: 0.107 AC: 26844 AN: 251270 Hom.: 2108 AF XY: 0.102 AC XY: 13853 AN XY: 135830

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0369

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.107 AC: 156549 AN: 1461796 Hom.: 9825 Cov.: 33 AF XY: 0.105 AC XY: 76247 AN XY: 727214

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.0284

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0404

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.0892

GnomAD4 genome AF: 0.0910 AC: 13848 AN: 152118 Hom.: 943 Cov.: 32 AF XY: 0.0934 AC XY: 6942 AN XY: 74358

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.0276

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0353

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0716

Alfa AF: 0.100 Hom.: 2213

Bravo AF: 0.0849

TwinsUK AF: 0.111 AC: 410

ALSPAC AF: 0.105 AC: 403

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.108 AC: 925

ExAC AF: 0.100 AC: 12142

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.0967

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 18, 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	0.18
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.00081	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.087
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.24		Gain of solvent accessibility (P = 0.0128);
MPC		0.69
ClinPred		0.078	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1799969; hg19: chr19-10394792; COSMIC: COSV53424452; COSMIC: COSV53424452;