rs2304237

Positions:

• chr19-10335892-T-C
• chr19-10335892-T-G

Variant summary

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

The NM_002162.5(ICAM3):​c.428A>G​(p.Asp143Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,600,568 control chromosomes in the GnomAD database, including 39,521 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 0.20 (3191 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36330 hom.)
• Consequence: ICAM3 NM_002162.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.621

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=0.009690255).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICAM3	NM_002162.5	c.428A>G	p.Asp143Gly	missense_variant	3/7	ENST00000160262.10	NP_002153.2
ICAM3	NM_001320606.2	c.197A>G	p.Asp66Gly	missense_variant	3/7		NP_001307535.1
ICAM3	NM_001320605.2	c.428A>G	p.Asp143Gly	missense_variant	3/6		NP_001307534.1
ICAM3	NM_001320608.2	c.-673A>G		5_prime_UTR_variant	3/6		NP_001307537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICAM3	ENST00000160262.10	c.428A>G	p.Asp143Gly	missense_variant	3/7	1	NM_002162.5	ENSP00000160262	P1
	ENST00000612689.1	n.2457T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30617 AN: 151962 Hom.: 3193 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.215 AC: 48901 AN: 227752 Hom.: 5390 AF XY: 0.222 AC XY: 27649 AN XY: 124562

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.117

Gnomad SAS exome AF: 0.274

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.221 AC: 320741 AN: 1448488 Hom.: 36330 Cov.: 35 AF XY: 0.224 AC XY: 161169 AN XY: 720220

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.201 AC: 30617 AN: 152080 Hom.: 3191 Cov.: 32 AF XY: 0.201 AC XY: 14918 AN XY: 74352

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.221

Alfa AF: 0.231 Hom.: 5448

Bravo AF: 0.197

TwinsUK AF: 0.214 AC: 792

ALSPAC AF: 0.234 AC: 901

ESP6500AA AF: 0.164 AC: 721

ESP6500EA AF: 0.221 AC: 1901

ExAC AF: 0.209 AC: 25140

Asia WGS AF: 0.190 AC: 663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.65
DEOGEN2	Benign	0.056	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.35	T;T;T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-3.3	N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	6.3	N;.;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.081
MPC		0.53
ClinPred		0.0046	T
GERP RS		5.0
Varity_R		0.073
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2304237; hg19: chr19-10446568; COSMIC: COSV50328285; COSMIC: COSV50328285;