Genetic Variant NM_001544.5:c.622G>C (chr19-10287763-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001544.5(ICAM4):c.622G>C(p.Val208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,613,746 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 3 hom. )

Consequence

ICAM4
NM_001544.5 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.477

Publications

3 publications found

Variant links:

Genes affected

ICAM4 (HGNC:5347): (intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)) This gene encodes the Landsteiner-Wiener (LW) blood group antigen(s) that belongs to the immunoglobulin (Ig) superfamily, and that shares similarity with the intercellular adhesion molecule (ICAM) protein family. This ICAM protein contains 2 Ig-like C2-type domains and binds to the leukocyte adhesion LFA-1 protein. The molecular basis of the LW(A)/LW(B) blood group antigens is a single aa variation at position 100; Gln-100=LW(A) and Arg-100=LW(B). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ICAM4 links:

ICAM4-AS1 (HGNC:55990): (ICAM4 antisense RNA 1)

ICAM4-AS1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033723414).

BP6

Variant 19-10287763-G-C is Benign according to our data. Variant chr19-10287763-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3037227.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00461 (701/152224) while in subpopulation AFR AF = 0.0161 (667/41536). AF 95% confidence interval is 0.015. There are 4 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 BG gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001544.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ICAM4	NM_001544.5	MANE Select	c.622G>C	p.Val208Leu	missense	Exon 2 of 3	NP_001535.1	Q14773-1
ICAM4	NM_001039132.3		c.545G>C	p.Arg182Pro	missense	Exon 2 of 3	NP_001034221.1	U5U6P8
ICAM4-AS1	NR_186335.1		n.1257C>G		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ICAM4	ENST00000380770.5	TSL:1 MANE Select	c.622G>C	p.Val208Leu	missense	Exon 2 of 3	ENSP00000370147.2	Q14773-1
ICAM4	ENST00000340992.4	TSL:1	c.545G>C	p.Arg182Pro	missense	Exon 2 of 3	ENSP00000342114.3	Q14773-3
ICAM4	ENST00000929145.1		c.652G>C	p.Val218Leu	missense	Exon 2 of 3	ENSP00000599204.1

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

701

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00109

AC:

273

AN:

251126

AF XY:

0.000862

show subpopulations

Gnomad AFR exome

AF:

0.0152

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000465

AC:

680

AN:

1461522

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

277

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.0171

AC:

572

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53054

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1112012

Other (OTH)

AF:

0.000679

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00461

AC:

701

AN:

152224

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

331

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0161

AC:

667

AN:

41536

American (AMR)

AF:

0.00170

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000246

Hom.:

Bravo

AF:

0.00539

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00144

AC:

175

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ICAM4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.1

(source)

DANN

Benign

0.74

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.90

PhyloP100

-0.48

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

REVEL

Benign

0.034

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.15

MVP

0.13

MPC

1.3

ClinPred

0.072

GERP RS

-7.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.047

gMVP

0.56

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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