19-10293112-C-A

Variant names:

• chr19-10293112-C-A
• rs202091893
• NM_003259.4:c.1331C>A

Variant summary

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

The NM_003259.4(ICAM5):​c.1331C>A​(p.Ala444Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ICAM5 NM_003259.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.234

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICAM5	NM_003259.4	c.1331C>A	p.Ala444Glu	missense_variant	Exon 6 of 11	ENST00000221980.5	NP_003250.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICAM5	ENST00000221980.5	c.1331C>A	p.Ala444Glu	missense_variant	Exon 6 of 11	1	NM_003259.4	ENSP00000221980.3
ICAM5	ENST00000586480.1	c.956C>A	p.Ala319Glu	missense_variant	Exon 4 of 9	1		ENSP00000516504.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000820 AC: 2 AN: 243976 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456636 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 724388

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.017
Sift	Benign	0.47	T
Sift4G	Benign	0.44	T
Polyphen		0.010	B
Vest4		0.27
MutPred		0.48		Gain of catalytic residue at A444 (P = 0.0213);
MVP		0.14
ClinPred		0.036	T
GERP RS		1.7
Varity_R		0.078
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs202091893; hg19: chr19-10403788;