rs77493670

Positions:

• chr19-10287311-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001544.5(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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Affects (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0051 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (49 hom.)
• Consequence: ICAM4 NM_001544.5 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 2.52

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)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICAM4	NM_001544.5	c.299A>G	p.Gln100Arg	missense_variant	1/3	ENST00000380770.5	NP_001535.1
ICAM4	NM_001039132.3	c.299A>G	p.Gln100Arg	missense_variant	1/3		NP_001034221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICAM4	ENST00000380770.5	c.299A>G	p.Gln100Arg	missense_variant	1/3	1	NM_001544.5	ENSP00000370147	P2
ICAM4	ENST00000340992.4	c.299A>G	p.Gln100Arg	missense_variant	1/3	1		ENSP00000342114
ICAM4-AS1	ENST00000589379.1	n.1709T>C		non_coding_transcript_exon_variant	1/1
ICAM4	ENST00000393717.2	c.299A>G	p.Gln100Arg	missense_variant	1/2	2		ENSP00000377320	A2

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

GnomAD3 exomes AF: 0.00487 AC: 1214 AN: 249518 Hom.: 12 AF XY: 0.00490 AC XY: 664 AN XY: 135388

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0297

Gnomad4 NFE exome AF: 0.00280

Gnomad4 OTH exome AF: 0.00291

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

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00412 Hom.: 7

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

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Landsteiner-Wiener phenotype Other:1

Affects, no assertion criteria provided

literature only

OMIM

Aug 15, 1995

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.091	T;D;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.94	P;.;D
Vest4		0.53
MVP		0.28
MPC		1.2
ClinPred		0.028	T
GERP RS		4.1
Varity_R		0.25
gMVP		0.35

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

LitVar

Other links and lift over

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