19-10292242-A-T

Variant names:

• chr19-10292242-A-T
• NM_003259.4:c.881A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003259.4(ICAM5):​c.881A>T​(p.Gln294Leu) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q294E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ICAM5 NM_003259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• Publications: 0 publications found

Genes affected

ICAM5 (HGNC:5348): (intercellular adhesion molecule 5) 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 expressed on the surface of telencephalic neurons and displays two types of adhesion activity, homophilic binding between neurons and heterophilic binding between neurons and leukocytes. It may be a critical component in neuron-microglial cell interactions in the course of normal development or as part of neurodegenerative diseases. [provided by RefSeq, Jul 2008]

ENSG00000294616 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08593178).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003259.4. 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
	ICAM5	NM_003259.4	MANE Select	c.881A>T	p.Gln294Leu	missense	Exon 4 of 11	NP_003250.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM5	ENST00000221980.5	TSL:1 MANE Select	c.881A>T	p.Gln294Leu	missense	Exon 4 of 11	ENSP00000221980.3	Q9UMF0
	ICAM5	ENST00000586480.1	TSL:1	c.506A>T	p.Gln169Leu	missense	Exon 2 of 9	ENSP00000516504.1	A0A9L9PXE8
	ICAM5	ENST00000948402.1		c.82+2117A>T		intron	N/A	ENSP00000618461.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.1
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.086
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.37
MutPred		0.39		Loss of disorder (P = 0.0518)
MVP		0.30
ClinPred		0.26	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.51
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr19-10402918;