21-44903482-C-A

Position:

• chr21-44903482-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000211.5(ITGB2):​c.382G>T​(p.Asp128Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D128N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.54

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 14 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 strand (size 7) in uniprot entity ITB2_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-44903482-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9467.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 21-44903482-C-A is Pathogenic according to our data. Variant chr21-44903482-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 68215.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-44903482-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB2	NM_000211.5	c.382G>T	p.Asp128Tyr	missense_variant	5/16	ENST00000652462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB2	ENST00000652462.1	c.382G>T	p.Asp128Tyr	missense_variant	5/16		NM_000211.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukocyte adhesion deficiency 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 16, 2023	This missense change has been observed in individual(s) with leukocyte adhesion deficiency type 1 (LAD1) (PMID: 20549317, 32279896). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 128 of the ITGB2 protein (p.Asp128Tyr). ClinVar contains an entry for this variant (Variation ID: 68215). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp128 amino acid residue in ITGB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1590804, 24338230, 26497373; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ITGB2 function (PMID: 28445705). 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. -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.2	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;.;D
Vest4		1.0
MutPred		0.94		Gain of methylation at K123 (P = 0.0626);Gain of methylation at K123 (P = 0.0626);Gain of methylation at K123 (P = 0.0626);Gain of methylation at K123 (P = 0.0626);Gain of methylation at K123 (P = 0.0626);.;Gain of methylation at K123 (P = 0.0626);Gain of methylation at K123 (P = 0.0626);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852615; hg19: chr21-46323397;