19-10334211-C-G

Variant names:

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

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>C​(p.Ala464Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ICAM3 NM_002162.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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, 0.9

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.1390G>C	p.Ala464Pro	missense	Exon 6 of 7	NP_002153.2	P32942
	ICAM3	NM_001320606.2		c.1159G>C	p.Ala387Pro	missense	Exon 6 of 7	NP_001307535.1
	ICAM3	NM_001320605.2		c.1102G>C	p.Ala368Pro	missense	Exon 5 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.1390G>C	p.Ala464Pro	missense	Exon 6 of 7	ENSP00000160262.3	P32942
	ICAM3	ENST00000589261.5	TSL:1	n.1692G>C		non_coding_transcript_exon	Exon 6 of 7
	ICAM3	ENST00000912542.1		c.847G>C	p.Ala283Pro	missense	Exon 4 of 5	ENSP00000582601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.77		Gain of glycosylation at A464 (P = 0.0424)
MVP		0.42
MPC		1.4
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.94
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;