rs1056538

Variant names:

• chr19-10292262-G-A
• rs1056538
• NM_003259.4:c.901G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003259.4(ICAM5):​c.901G>A​(p.Val301Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,612,270 control chromosomes in the GnomAD database, including 117,960 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (8971 hom., cov: 33)
  • Exomes 𝑓: 0.38 (108989 hom.)
• Consequence: ICAM5 NM_003259.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8416514E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICAM5	NM_003259.4	c.901G>A	p.Val301Ile	missense_variant	Exon 4 of 11	ENST00000221980.5	NP_003250.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICAM5	ENST00000221980.5	c.901G>A	p.Val301Ile	missense_variant	Exon 4 of 11	1	NM_003259.4	ENSP00000221980.3
ICAM5	ENST00000586480.1	c.526G>A	p.Val176Ile	missense_variant	Exon 2 of 9	1		ENSP00000516504.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47491 AN: 152134 Hom.: 8973 Cov.: 33

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.385 AC: 95628 AN: 248350 AF XY: 0.388

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.384

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.381 AC: 555902 AN: 1460018 Hom.: 108989 Cov.: 48 AF XY: 0.382 AC XY: 277140 AN XY: 726328

Gnomad4 AFR exome AF: 0.0822 AC: 2752 AN: 33474

Gnomad4 AMR exome AF: 0.566 AC: 25268 AN: 44640

Gnomad4 ASJ exome AF: 0.383 AC: 9997 AN: 26132

Gnomad4 EAS exome AF: 0.284 AC: 11276 AN: 39670

Gnomad4 SAS exome AF: 0.403 AC: 34772 AN: 86244

Gnomad4 FIN exome AF: 0.364 AC: 19003 AN: 52220

Gnomad4 NFE exome AF: 0.385 AC: 428464 AN: 1111540

Gnomad4 Remaining exome AF: 0.369 AC: 22276 AN: 60346

GnomAD4 genome AF: 0.312 AC: 47486 AN: 152252 Hom.: 8971 Cov.: 33 AF XY: 0.313 AC XY: 23319 AN XY: 74442

Gnomad4 AFR AF: 0.0959 AC: 0.0959171 AN: 0.0959171

Gnomad4 AMR AF: 0.463 AC: 0.462832 AN: 0.462832

Gnomad4 ASJ AF: 0.389 AC: 0.388537 AN: 0.388537

Gnomad4 EAS AF: 0.242 AC: 0.242166 AN: 0.242166

Gnomad4 SAS AF: 0.400 AC: 0.400166 AN: 0.400166

Gnomad4 FIN AF: 0.358 AC: 0.35841 AN: 0.35841

Gnomad4 NFE AF: 0.393 AC: 0.392915 AN: 0.392915

Gnomad4 OTH AF: 0.359 AC: 0.359242 AN: 0.359242

Alfa AF: 0.349 Hom.: 4344

Bravo AF: 0.312

TwinsUK AF: 0.375 AC: 1389

ALSPAC AF: 0.375 AC: 1445

ESP6500AA AF: 0.0990 AC: 436

ESP6500EA AF: 0.389 AC: 3345

ExAC AF: 0.373 AC: 45233

Asia WGS AF: 0.335 AC: 1171 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.401

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.022	T
MetaRNN	Benign	0.00028	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.035
Sift	Benign	0.20	T
Sift4G	Benign	0.12	T
Polyphen		0.0060	B
Vest4		0.019
ClinPred		0.0055	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.16
Mutation Taster		=64/36	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1056538; hg19: chr19-10402938; COSMIC: COSV55746359; COSMIC: COSV55746359;