chr21-44901518-C-T

Variant names:

• chr21-44901518-C-T
• rs179363873
• NM_000211.5:c.715G>A

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.715G>A​(p.Ala239Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,860 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 the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ITGB2 NM_000211.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.45

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 helix (size 9) in uniprot entity ITB2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000211.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 21-44901518-C-T is Pathogenic according to our data. Variant chr21-44901518-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44901518-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB2	NM_000211.5	c.715G>A	p.Ala239Thr	missense_variant	Exon 6 of 16	ENST00000652462.1	NP_000202.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB2	ENST00000652462.1	c.715G>A	p.Ala239Thr	missense_variant	Exon 6 of 16		NM_000211.5	ENSP00000498780.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukocyte adhesion deficiency 1 Pathogenic:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the ITGB2 protein (p.Ala239Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with leukocyte adhesion deficiency type 1 (PMID: 20549317, 26639818, 33391282). ClinVar contains an entry for this variant (Variation ID: 68216). 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. Experimental studies have shown that this missense change affects ITGB2 function (PMID: 25514840). For these reasons, this variant has been classified as Pathogenic. -

not provided Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	.;.;T;.;.;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Vest4		0.96
MutPred		0.92		Gain of disorder (P = 0.1923);Gain of disorder (P = 0.1923);.;Gain of disorder (P = 0.1923);Gain of disorder (P = 0.1923);Gain of disorder (P = 0.1923);.;
MVP		0.95
MPC		1.0
ClinPred		1.0	D
GERP RS		4.2
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs179363873; hg19: chr21-46321433;