rs7258015

chr19-10338682-T-C

Variant summary

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

The NM_002162.5(ICAM3):c.343A>G(p.Arg115Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,612,954 control chromosomes in the GnomAD database, including 40,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 0.20 (3233 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37430 hom.)
• Consequence: ICAM3 NM_002162.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001600
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013009906).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICAM3	NM_002162.5	c.343A>G	p.Arg115Gly	missense_variant, splice_region_variant	2/7	ENST00000160262.10
ICAM3	NM_001320606.2	c.112A>G	p.Arg38Gly	missense_variant, splice_region_variant	2/7
ICAM3	NM_001320605.2	c.343A>G	p.Arg115Gly	missense_variant, splice_region_variant	2/6
ICAM3	NM_001320608.2	c.-758A>G		splice_region_variant, 5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICAM3	ENST00000160262.10	c.343A>G	p.Arg115Gly	missense_variant, splice_region_variant	2/7	1	NM_002162.5	P1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30759 AN: 152066 Hom.: 3235 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.215 AC: 53879 AN: 250222 Hom.: 6048 AF XY: 0.222 AC XY: 30054 AN XY: 135336

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.273

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.224 AC: 326737 AN: 1460770 Hom.: 37430 Cov.: 32 AF XY: 0.226 AC XY: 164241 AN XY: 726694

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.134

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.202 AC: 30753 AN: 152184 Hom.: 3233 Cov.: 32 AF XY: 0.201 AC XY: 14950 AN XY: 74380

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.222

Alfa AF: 0.227 Hom.: 8158

Bravo AF: 0.198

TwinsUK AF: 0.218 AC: 808

ALSPAC AF: 0.237 AC: 912

ESP6500AA AF: 0.169 AC: 745

ESP6500EA AF: 0.229 AC: 1967

ExAC AF: 0.218 AC: 26521

Asia WGS AF: 0.188 AC: 655 AN: 3478

EpiCase AF: 0.238

EpiControl AF: 0.238

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.68
Dann	Benign	0.79
DEOGEN2	Benign	0.070	T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.19	T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0e-37	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;.;.;.
REVEL	Benign	0.059
Sift	Benign	0.35	T;.;.;.
Sift4G	Benign	0.40	T;T;.;.
Polyphen		0.0	B;.;.;.
Vest4		0.046
MPC		0.53
ClinPred		0.021	T
GERP RS		-12
Varity_R		0.14
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.060		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: rs7258015; hg19: chr19-10449358; COSMIC: COSV50329062; COSMIC: COSV50329062;