chr19-10334702-C-A

Variant names:

• chr19-10334702-C-A
• rs2040566712
• NM_002162.5:c.1018G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002162.5(ICAM3):​c.1018G>T​(p.Ala340Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ICAM3 NM_002162.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.35
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1018G>T	p.Ala340Ser	missense	Exon 5 of 7	NP_002153.2	P32942
	ICAM3	NM_001320606.2		c.787G>T	p.Ala263Ser	missense	Exon 5 of 7	NP_001307535.1
	ICAM3	NM_001320605.2		c.730G>T	p.Ala244Ser	missense	Exon 4 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.1018G>T	p.Ala340Ser	missense	Exon 5 of 7	ENSP00000160262.3	P32942
	ICAM3	ENST00000589261.5	TSL:1	n.1320G>T		non_coding_transcript_exon	Exon 5 of 7
	ICAM3	ENST00000706691.1		c.10G>T	p.Ala4Ser	missense	Exon 1 of 3	ENSP00000516505.1	A0A9L9PXS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460986 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726816

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

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	Benign	0.075
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.9
DANN	Benign	0.82
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		-5.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.055
Sift	Benign	0.37	T
Sift4G	Benign	0.35	T
Polyphen		0.25	B
Vest4		0.16
MutPred		0.34		Gain of glycosylation at A340 (P = 0.0545)
MVP		0.095
MPC		0.37
ClinPred		0.10	T
GERP RS		-11
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.070
gMVP		0.42
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2040566712; hg19: chr19-10445378;