Genetic Variant NM_000201.3:c.1055C>T (chr19-10284532-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000201.3(ICAM1):c.1055C>T(p.Pro352Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,613,982 control chromosomes in the GnomAD database, including 684 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.021 ( 39 hom., cov: 32)

Exomes 𝑓: 0.028 ( 645 hom. )

Consequence

ICAM1
NM_000201.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.61

Publications

25 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035290718).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0214 (3258/152220) while in subpopulation NFE AF = 0.0295 (2009/67992). AF 95% confidence interval is 0.0285. There are 39 homozygotes in GnomAd4. There are 1532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000201.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM1	NM_000201.3	MANE Select	c.1055C>T	p.Pro352Leu	missense	Exon 5 of 7	NP_000192.2	A0A384MEK5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ICAM1	ENST00000264832.8	TSL:1 MANE Select	c.1055C>T	p.Pro352Leu	missense	Exon 5 of 7	ENSP00000264832.2	P05362
ICAM1	ENST00000902798.1		c.1055C>T	p.Pro352Leu	missense	Exon 5 of 6	ENSP00000572857.1
ICAM1	ENST00000935832.1		c.791C>T	p.Pro264Leu	missense	Exon 4 of 6	ENSP00000605891.1

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3257

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00999

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0248

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0215

AC:

5356

AN:

249536

AF XY:

0.0212

show subpopulations

Gnomad AFR exome

AF:

0.00919

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.0500

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0298

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0277

AC:

40425

AN:

1461762

Hom.:

645

Cov.:

AF XY:

0.0268

AC XY:

19467

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00795

AC:

266

AN:

33480

American (AMR)

AF:

0.0170

AC:

762

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0494

AC:

1292

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39658

South Asian (SAS)

AF:

0.00543

AC:

468

AN:

86258

European-Finnish (FIN)

AF:

0.0231

AC:

1231

AN:

53382

Middle Eastern (MID)

AF:

0.0180

AC:

104

AN:

5766

European-Non Finnish (NFE)

AF:

0.0311

AC:

34550

AN:

1111980

Other (OTH)

AF:

0.0290

AC:

1749

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2628

5257

7885

10514

13142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1300

2600

3900

5200

6500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0214

AC:

3258

AN:

152220

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1532

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00999

AC:

415

AN:

41544

American (AMR)

AF:

0.0248

AC:

379

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

169

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00642

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0166

AC:

176

AN:

10616

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0295

AC:

2009

AN:

67992

Other (OTH)

AF:

0.0298

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

164

327

491

654

818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0272

Hom.:

202

Bravo

AF:

0.0224

TwinsUK

AF:

0.0329

AC:

122

ALSPAC

AF:

0.0314

AC:

121

ESP6500AA

AF:

0.00954

AC:

ESP6500EA

AF:

0.0292

AC:

251

ExAC

AF:

0.0216

AC:

2615

EpiCase

AF:

0.0334

EpiControl

AF:

0.0324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.3

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

-2.6

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.057

Sift

Benign

0.072

Sift4G

Benign

0.068

Polyphen

0.96

Vest4

0.17

MPC

0.27

ClinPred

0.042

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.36

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over