Variant 19-10291534-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003259.4(ICAM5):c.398C>A(p.Pro133Gln) 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 1,460,262 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: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ICAM5
NM_003259.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.218

Variant links:

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]

ICAM5 links:

ICAM5 (HGNC:):

ICAM5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26279795).

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICAM5	NM_003259.4 linkuse as main transcript	c.398C>A	p.Pro133Gln	missense_variant	3/11	ENST00000221980.5	NP_003250.3	Q9UMF0Q8N6I2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ICAM5	ENST00000221980.5 linkuse as main transcript	c.398C>A	p.Pro133Gln	missense_variant	3/11	1	NM_003259.4	ENSP00000221980.3	Q9UMF0
ICAM5	ENST00000586480.1 linkuse as main transcript	c.23C>A	p.Pro8Gln	missense_variant	1/9	1		ENSP00000516504.1	A0A9L9PXE8
ICAM5	ENST00000586004.1 linkuse as main transcript	n.393C>A		non_coding_transcript_exon_variant	3/3	4
ICAM5	ENST00000587398.1 linkuse as main transcript	n.411C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000250

AC:

AN:

239910

Hom.:

AF XY:

0.0000379

AC XY:

AN XY:

132040

show subpopulations

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:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000473

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1460262

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726414

show subpopulations

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:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000731

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2024

The c.398C>A (p.P133Q) alteration is located in exon 3 (coding exon 3) of the ICAM5 gene. This alteration results from a C to A substitution at nucleotide position 398, causing the proline (P) at amino acid position 133 to be replaced by a glutamine (Q). 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

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

D;.

Eigen

Benign

0.014

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.4

D;.

REVEL

Benign

0.13

Sift

Benign

0.12

T;.

Sift4G

Uncertain

0.016

D;T

Polyphen

1.0

D;.

Vest4

0.52

MutPred

0.31

Gain of sheet (P = 0.1208);.;

MVP

0.44

ClinPred

0.84

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.50

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over