chr19-10293136-T-C

Variant names:

• chr19-10293136-T-C
• rs143181516
• NM_003259.4:c.1355T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003259.4(ICAM5):​c.1355T>C​(p.Leu452Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,610,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ICAM5 NM_003259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.915
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2675496).
• BS2: High AC in GnomAd4 at 11 AD gene.

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.1355T>C	p.Leu452Pro	missense	Exon 6 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.1355T>C	p.Leu452Pro	missense	Exon 6 of 11	ENSP00000221980.3	Q9UMF0
	ICAM5	ENST00000586480.1	TSL:1	c.980T>C	p.Leu327Pro	missense	Exon 4 of 9	ENSP00000516504.1	A0A9L9PXE8
	ICAM5	ENST00000948402.1		c.83-2210T>C		intron	N/A	ENSP00000618461.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000163 AC: 4 AN: 246122 AF XY: 0.00000747

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1457906 Hom.: 0 Cov.: 39 AF XY: 0.00000276 AC XY: 2 AN XY: 724932

African (AFR) AF: 0.000299 AC: 10 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51932

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110430

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152380 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74516

African (AFR) AF: 0.000264 AC: 11 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000849 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.58
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.92
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.36
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.80
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs143181516; hg19: chr19-10403812;