19-10287311-A-G

Variant names:

• chr19-10287311-A-G
• rs77493670
• NM_001544.5:c.299A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001039132.3(ICAM4):​c.299A>G​(p.Gln100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,613,690 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Affects (no stars).

• Frequency:
  • Genomes: 𝑓 0.0051 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (49 hom.)
• Consequence: ICAM4 NM_001039132.3 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 2.52
• Publications: 12 publications found

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

LIMASI (HGNC:56357): (lncRNA inflammatory and mucous response associated, antisense to ICAM1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009648979).
• BS2: High Homozygotes in GnomAd4 at 12 BG gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039132.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM4	NM_001544.5	MANE Select	c.299A>G	p.Gln100Arg	missense	Exon 1 of 3	NP_001535.1
	ICAM4	NM_001039132.3		c.299A>G	p.Gln100Arg	missense	Exon 1 of 3	NP_001034221.1
	ICAM4-AS1	NR_186335.1		n.1709T>C		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM4	ENST00000380770.5	TSL:1 MANE Select	c.299A>G	p.Gln100Arg	missense	Exon 1 of 3	ENSP00000370147.2
	ICAM4	ENST00000340992.4	TSL:1	c.299A>G	p.Gln100Arg	missense	Exon 1 of 3	ENSP00000342114.3
	ICAM4	ENST00000929145.1		c.299A>G	p.Gln100Arg	missense	Exon 1 of 3	ENSP00000599204.1

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 781 AN: 152182 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00623

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00487 AC: 1214 AN: 249518 AF XY: 0.00490

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00839

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0289

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00349 AC: 5096 AN: 1461390 Hom.: 49 Cov.: 31 AF XY: 0.00359 AC XY: 2613 AN XY: 727022

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 204 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86248

European-Finnish (FIN) AF: 0.0297 AC: 1575 AN: 52998

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00280 AC: 3112 AN: 1111968

Other (OTH) AF: 0.00291 AC: 176 AN: 60390

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152300 Hom.: 12 Cov.: 32 AF XY: 0.00618 AC XY: 460 AN XY: 74478

African (AFR) AF: 0.000168 AC: 7 AN: 41576

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0290 AC: 308 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00622 AC: 423 AN: 68012

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00390 Hom.: 13

Bravo AF: 0.00198

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00461 AC: 560

EpiCase AF: 0.00371

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Affects

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Landsteiner-Wiener phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.091	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.53
MVP		0.28
MPC		1.2
ClinPred		0.028	T
GERP RS		4.1
PromoterAI		-0.036	Neutral
Varity_R		0.25
gMVP		0.35
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs77493670; hg19: chr19-10397987; COSMIC: COSV53425335; COSMIC: COSV53425335;