rs7258015

Variant names:

• chr19-10338682-T-C
• rs7258015
• NM_002162.5:c.343A>G

Variant summary

Our verdict is Benign. The variant received -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. 17/23 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. Synonymous variant affecting the same amino acid position (i.e. R115R) has been classified as Uncertain significance.

• 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
• Publications: 49 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM3	NM_002162.5	MANE Select	c.343A>G	p.Arg115Gly	missense splice_region	Exon 2 of 7	NP_002153.2	P32942
	ICAM3	NM_001320606.2		c.112A>G	p.Arg38Gly	missense splice_region	Exon 2 of 7	NP_001307535.1
	ICAM3	NM_001320605.2		c.343A>G	p.Arg115Gly	missense splice_region	Exon 2 of 6	NP_001307534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM3	ENST00000160262.10	TSL:1 MANE Select	c.343A>G	p.Arg115Gly	missense splice_region	Exon 2 of 7	ENSP00000160262.3	P32942
	ICAM3	ENST00000589261.5	TSL:1	n.645A>G		splice_region non_coding_transcript_exon	Exon 2 of 7
	ICAM3	ENST00000912542.1		c.343A>G	p.Arg115Gly	missense splice_region	Exon 2 of 5	ENSP00000582601.1

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

GnomAD2 exomes AF: 0.215 AC: 53879 AN: 250222 AF XY: 0.222

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 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

African (AFR) AF: 0.159 AC: 5319 AN: 33472

American (AMR) AF: 0.184 AC: 8229 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6433 AN: 26122

East Asian (EAS) AF: 0.134 AC: 5312 AN: 39672

South Asian (SAS) AF: 0.273 AC: 23519 AN: 86240

European-Finnish (FIN) AF: 0.206 AC: 10952 AN: 53242

Middle Eastern (MID) AF: 0.269 AC: 1545 AN: 5754

European-Non Finnish (NFE) AF: 0.227 AC: 252416 AN: 1111186

Other (OTH) AF: 0.216 AC: 13012 AN: 60370

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

African (AFR) AF: 0.160 AC: 6645 AN: 41520

American (AMR) AF: 0.179 AC: 2736 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 854 AN: 3472

East Asian (EAS) AF: 0.119 AC: 615 AN: 5178

South Asian (SAS) AF: 0.253 AC: 1223 AN: 4830

European-Finnish (FIN) AF: 0.207 AC: 2192 AN: 10590

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15685 AN: 68004

Other (OTH) AF: 0.222 AC: 469 AN: 2114

Alfa AF: 0.223 Hom.: 15620

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 v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-2.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.059
Sift	Benign	0.35	T
Sift4G	Benign	0.40	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
Mutation Taster		=75/25	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7258015; hg19: chr19-10449358; COSMIC: COSV50329062; COSMIC: COSV50329062;