19-10335892-T-C

Variant names:

• chr19-10335892-T-C
• rs2304237
• NM_002162.5:c.428A>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.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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 56 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]

ENSG00000274425 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ICAM3	NM_002162.5	c.428A>G	p.Asp143Gly	missense_variant	Exon 3 of 7	ENST00000160262.10	NP_002153.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICAM3	ENST00000160262.10	c.428A>G	p.Asp143Gly	missense_variant	Exon 3 of 7	1	NM_002162.5	ENSP00000160262.3

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

GnomAD2 exomes AF: 0.215 AC: 48901 AN: 227752 AF XY: 0.222

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 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

African (AFR) AF: 0.159 AC: 5331 AN: 33424

American (AMR) AF: 0.182 AC: 7865 AN: 43120

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 6084 AN: 25922

East Asian (EAS) AF: 0.133 AC: 5245 AN: 39368

South Asian (SAS) AF: 0.275 AC: 23404 AN: 85222

European-Finnish (FIN) AF: 0.200 AC: 9382 AN: 46886

Middle Eastern (MID) AF: 0.265 AC: 1527 AN: 5754

European-Non Finnish (NFE) AF: 0.225 AC: 249113 AN: 1108728

Other (OTH) AF: 0.213 AC: 12790 AN: 60064

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

African (AFR) AF: 0.161 AC: 6695 AN: 41508

American (AMR) AF: 0.179 AC: 2738 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 814 AN: 3468

East Asian (EAS) AF: 0.116 AC: 599 AN: 5156

South Asian (SAS) AF: 0.259 AC: 1244 AN: 4812

European-Finnish (FIN) AF: 0.206 AC: 2181 AN: 10588

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

European-Non Finnish (NFE) AF: 0.229 AC: 15546 AN: 67956

Other (OTH) AF: 0.221 AC: 466 AN: 2112

Alfa AF: 0.227 Hom.: 6528

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;.;.
PhyloP100		0.62
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
PromoterAI		0.078	Neutral
Varity_R		0.073
gMVP		0.71
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304237; hg19: chr19-10446568; COSMIC: COSV50328285; COSMIC: COSV50328285;