chr19-10334288-T-G

Position:

• chr19-10334288-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002162.5(ICAM3):​c.1313A>C​(p.Glu438Ala) 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 benign outcome for this variant. 13/21 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)
• Consequence: ICAM3 NM_002162.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.657

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.120690346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICAM3	NM_002162.5	c.1313A>C	p.Glu438Ala	missense_variant	6/7	ENST00000160262.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICAM3	ENST00000160262.10	c.1313A>C	p.Glu438Ala	missense_variant	6/7	1	NM_002162.5	P1
	ENST00000612689.1	n.853T>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.1313A>C (p.E438A) alteration is located in exon 6 (coding exon 6) of the ICAM3 gene. This alteration results from a A to C substitution at nucleotide position 1313, causing the glutamic acid (E) at amino acid position 438 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.082	T;T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.49	T;T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;.;.;.
REVEL	Benign	0.051
Sift	Benign	0.13	T;.;.;.
Sift4G	Benign	0.22	T;T;T;.
Polyphen		0.47	P;.;.;.
Vest4		0.14
MutPred		0.33		Loss of ubiquitination at K437 (P = 0.0382);.;.;.;
MVP		0.39
MPC		0.96
ClinPred		0.68	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs1599309534; hg19: chr19-10444964;