rs2230399

Positions:

• chr19-10333927-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002162.5(ICAM3):​c.1574G>C​(p.Ser525Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,613,934 control chromosomes in the GnomAD database, including 7,305 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1189 hom., cov: 32)
  • Exomes 𝑓: 0.086 (6116 hom.)
• Consequence: ICAM3 NM_002162.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.221

Genes affected

ICAM3 (HGNC:5346): (intercellular adhesion molecule 3) The protein encoded by this gene is a member of the intercellular adhesion molecule (ICAM) family. All ICAM proteins are type I transmembrane glycoproteins, contain 2-9 immunoglobulin-like C2-type domains, and bind to the leukocyte adhesion LFA-1 protein. This protein is constitutively and abundantly expressed by all leucocytes and may be the most important ligand for LFA-1 in the initiation of the immune response. It functions not only as an adhesion molecule, but also as a potent signalling molecule. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035166442).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICAM3	NM_002162.5	c.1574G>C	p.Ser525Thr	missense_variant	7/7	ENST00000160262.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICAM3	ENST00000160262.10	c.1574G>C	p.Ser525Thr	missense_variant	7/7	1	NM_002162.5	P1
	ENST00000612689.1	n.492C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16713 AN: 152022 Hom.: 1177 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0618

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0755

Gnomad FIN AF: 0.0782

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0840

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.0751 AC: 18873 AN: 251468 Hom.: 984 AF XY: 0.0743 AC XY: 10100 AN XY: 135908

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0390

Gnomad ASJ exome AF: 0.0397

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.0748

Gnomad FIN exome AF: 0.0799

Gnomad NFE exome AF: 0.0815

Gnomad OTH exome AF: 0.0655

GnomAD4 exome AF: 0.0859 AC: 125635 AN: 1461794 Hom.: 6116 Cov.: 34 AF XY: 0.0850 AC XY: 61811 AN XY: 727192

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.0422

Gnomad4 ASJ exome AF: 0.0412

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0781

Gnomad4 FIN exome AF: 0.0791

Gnomad4 NFE exome AF: 0.0890

Gnomad4 OTH exome AF: 0.0848

GnomAD4 genome AF: 0.110 AC: 16760 AN: 152140 Hom.: 1189 Cov.: 32 AF XY: 0.108 AC XY: 8068 AN XY: 74392

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.0617

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0753

Gnomad4 FIN AF: 0.0782

Gnomad4 NFE AF: 0.0840

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0810 Hom.: 472

Bravo AF: 0.113

TwinsUK AF: 0.0968 AC: 359

ALSPAC AF: 0.0859 AC: 331

ESP6500AA AF: 0.200 AC: 880

ESP6500EA AF: 0.0844 AC: 726

ExAC AF: 0.0789 AC: 9579

Asia WGS AF: 0.0480 AC: 166 AN: 3478

EpiCase AF: 0.0773

EpiControl AF: 0.0807

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.86
DEOGEN2	Benign	0.047	T;T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.38	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.041
Sift	Benign	0.21	T;.;.
Sift4G	Benign	0.14	T;T;T
Polyphen		0.68	P;.;.
Vest4		0.049
MPC		0.38
ClinPred		0.0049	T
GERP RS		0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs2230399; hg19: chr19-10444603; COSMIC: COSV50328770; COSMIC: COSV50328770;