19-10334211-C-T

Variant names:

• chr19-10334211-C-T
• rs2145092351
• NM_002162.5:c.1390G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002162.5(ICAM3):​c.1390G>A​(p.Ala464Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A464P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ICAM3 NM_002162.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICAM3	NM_002162.5	c.1390G>A	p.Ala464Thr	missense_variant	Exon 6 of 7	ENST00000160262.10	NP_002153.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICAM3	ENST00000160262.10	c.1390G>A	p.Ala464Thr	missense_variant	Exon 6 of 7	1	NM_002162.5	ENSP00000160262.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;T;T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;.;.
PhyloP100		1.3
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D;.;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.59
MutPred		0.79		Gain of disorder (P = 0.1125);.;.;
MVP		0.36
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.47
gMVP		0.71
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2145092351; hg19: chr19-10444887;