rs1799969

Variant names:

• chr19-10284116-G-A
• rs1799969
• NM_000201.3:c.721G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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 no assertion criteria provided 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

Our verdict: Benign. The variant received -13 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 no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
ICAM1	NM_000201.3	c.721G>A	p.Gly241Arg	missense_variant	Exon 4 of 7	ENST00000264832.8	NP_000192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICAM1	ENST00000264832.8	c.721G>A	p.Gly241Arg	missense_variant	Exon 4 of 7	1	NM_000201.3	ENSP00000264832.2
ICAM1	ENST00000423829.2	c.68-13G>A		intron_variant	Intron 1 of 4	2		ENSP00000413124.2
LIMASI	ENST00000592893.1	n.141+852C>T		intron_variant	Intron 1 of 2	3
ICAM1	ENST00000592686.1	n.*18G>A		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

GnomAD2 exomes AF: 0.107 AC: 26844 AN: 251270 AF XY: 0.102

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 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 AC: 553 AN: 33480

Gnomad4 AMR exome AF: 0.207 AC: 9263 AN: 44722

Gnomad4 ASJ exome AF: 0.0284 AC: 743 AN: 26136

Gnomad4 EAS exome AF: 0.000302 AC: 12 AN: 39700

Gnomad4 SAS exome AF: 0.0404 AC: 3487 AN: 86258

Gnomad4 FIN exome AF: 0.198 AC: 10581 AN: 53344

Gnomad4 NFE exome AF: 0.114 AC: 126398 AN: 1111992

Gnomad4 Remaining exome AF: 0.0892 AC: 5385 AN: 60396

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 AC: 0.0207591 AN: 0.0207591

Gnomad4 AMR AF: 0.149 AC: 0.149424 AN: 0.149424

Gnomad4 ASJ AF: 0.0276 AC: 0.0276498 AN: 0.0276498

Gnomad4 EAS AF: 0.00155 AC: 0.00154799 AN: 0.00154799

Gnomad4 SAS AF: 0.0353 AC: 0.0352551 AN: 0.0352551

Gnomad4 FIN AF: 0.205 AC: 0.205377 AN: 0.205377

Gnomad4 NFE AF: 0.116 AC: 0.116324 AN: 0.116324

Gnomad4 OTH AF: 0.0716 AC: 0.0716319 AN: 0.0716319

Alfa AF: 0.102 Hom.: 4486

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: no assertion criteria provided

Submissions by phenotype

ICAM1-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
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
Mutation Taster		=78/22	polymorphism (auto)

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;