Variant 19-10293014-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.1233C>A(p.Asp411Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ICAM5
NM_003259.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.39

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:

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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=0.118667156).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICAM5	NM_003259.4 linkuse as main transcript	c.1233C>A	p.Asp411Glu	missense_variant	6/11	ENST00000221980.5	NP_003250.3	Q9UMF0Q8N6I2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICAM5	ENST00000221980.5 linkuse as main transcript	c.1233C>A	p.Asp411Glu	missense_variant	6/11	1	NM_003259.4	ENSP00000221980.3		Q9UMF0
ICAM5	ENST00000586480.1 linkuse as main transcript	c.858C>A	p.Asp286Glu	missense_variant	4/9	1		ENSP00000516504.1		A0A9L9PXE8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458752

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725860

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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

Jul 25, 2024

The c.1233C>A (p.D411E) alteration is located in exon 6 (coding exon 6) of the ICAM5 gene. This alteration results from a C to A substitution at nucleotide position 1233, causing the aspartic acid (D) at amino acid position 411 to be replaced by a glutamic acid (E). 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

0.15

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.2

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.74

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.13

Sift

Benign

0.12

Sift4G

Uncertain

0.015

Polyphen

0.92

Vest4

0.13

MutPred

0.58

Gain of glycosylation at S413 (P = 0.1274);

MVP

0.12

ClinPred

0.64

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.13

gMVP

0.47

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

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