rs137852618

chr21-44900400-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000211.5(ITGB2):c.817G>A(p.Gly273Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000626 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. G273G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.76

Genes affected

ITGB2 (HGNC:6155): (integrin subunit beta 2) This gene encodes an integrin beta chain, which combines with multiple different alpha chains to form different integrin heterodimers. Integrins are integral cell-surface proteins that participate in cell adhesion as well as cell-surface mediated signalling. The encoded protein plays an important role in immune response and defects in this gene cause leukocyte adhesion deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_000211.5 (ITGB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a domain VWFA (size 239) in uniprot entity ITB2_HUMAN there are 70 pathogenic changes around while only 6 benign (92%) in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 21-44900400-C-T is Pathogenic according to our data. Variant chr21-44900400-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44900400-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB2	NM_000211.5	c.817G>A	p.Gly273Arg	missense_variant	7/16	ENST00000652462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB2	ENST00000652462.1	c.817G>A	p.Gly273Arg	missense_variant	7/16		NM_000211.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251282 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000629 AC: 92 AN: 1461768 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.0000636 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukocyte adhesion deficiency 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ITGB2 NM_000211.4 exon 7 p.Gly273Arg (c.817G>A): This variant has been reported in the literature in at least 3 individuals with Leukocyte Adhesion Deficiency Type-I (LAD-I) as homozygous or compound heterozygotes (Hogg 1999 PMID:9664339, Yamazaki-Nakashima 2015 PMID:25527966). This variant is present in 3/126630 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137852618). This variant is present in ClinVar (Variation ID:9471). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies suggest a deleterious effect of this variant, potentially impacting the cell surface expression of Beta-2 integrins (Hogg 1999 PMID:9664339, Guan 2015 PMID:25514840, Yamazaki-Nakashima 2015 PMID:25527966). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 20, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ITGB2 function (PMID: 9884339). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITGB2 protein function. ClinVar contains an entry for this variant (Variation ID: 9471). This missense change has been observed in individual(s) with leukocyte adhesion deficiency type 1 (PMID: 9884339, 30919141; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs137852618, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 273 of the ITGB2 protein (p.Gly273Arg). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2023

Published functional studies demonstrate a damaging effect through a lack of expression of LFA-1 on the surface of cells expressing this variant (Hogg et al., 1999; Yamazaki-Nakashimada et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17651379, 30312521, 30968598, 34310689, 10936446, 25527966, 22134107, 25514840, 25703682, 30919141, 9884339, 31965297, 32279896, 33391282, 33365035, 33240318) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Vest4		0.98
MutPred		0.96		Loss of ubiquitination at K274 (P = 0.0699);Loss of ubiquitination at K274 (P = 0.0699);.;Loss of ubiquitination at K274 (P = 0.0699);Loss of ubiquitination at K274 (P = 0.0699);Loss of ubiquitination at K274 (P = 0.0699);.;
MVP		0.97
MPC		0.82
ClinPred		1.0	D
GERP RS		5.0
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852618; hg19: chr21-46320315; COSMIC: COSV56609830; COSMIC: COSV56609830;