chr22-17209533-GC-G

Position:

• chr22-17209533-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000399837.8(ADA2):​c.144del​(p.Arg49GlyfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G48G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: ADA2 ENST00000399837.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.668

Genes affected

ADA2 (HGNC:1839): (adenosine deaminase 2) This gene encodes a member of a subfamily of the adenosine deaminase protein family. The encoded protein is one of two adenosine deaminases found in humans, which regulate levels of the signaling molecule, adenosine. The encoded protein is secreted from monocytes undergoing differentiation and may regulate cell proliferation and differentiation. This gene may be responsible for some of the phenotypic features associated with cat eye syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-17209533-GC-G is Pathogenic according to our data. Variant chr22-17209533-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 640066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17209533-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA2	NM_001282225.2	c.144del	p.Arg49GlyfsTer4	frameshift_variant	2/10	ENST00000399837.8	NP_001269154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8	c.144del	p.Arg49GlyfsTer4	frameshift_variant	2/10	1	NM_001282225.2	ENSP00000382731	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151912 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250912 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135722

Gnomad AFR exome AF: 0.0000618

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: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461248 Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 726954

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151912 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74188

Gnomad4 AFR AF: 0.0000725

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vasculitis due to ADA2 deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous p.Arg49GlyfsTer4 variant in ADA2 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 624611), in one individual with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 624611). The p.Arg49GlyfsTer4 variant in ADA2 has been previously reported in 4 unrelated individuals with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (PMID: 32909274, PMID: 35804211, PMID: 28522451, PMID: 27059682) and segregated with disease in 2 affected relatives from one family (PMID: 35804211), but has been identified in 0.007% (3/41374) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756881285). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 4 previously reported unrelated individuals (PMID: 32909274, PMID: 35804211, PMID: 28522451, PMID: 27059682), one was a homozygote (PMID: 35804211) and two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 27059682, ClinVar Variation ID: 1407177; PMID: 28522451, ClinVar Variation ID 189342), which increases the likelihood that the p.Arg49GlyfsTer4 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 640066) and has been interpreted as pathogenic by Invitae and Fulgent Genetics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 49 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ADA2 gene is strongly associated to autosomal recessive vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3_Strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change creates a premature translational stop signal (p.Arg49Glyfs*4) in the ADA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA2 are known to be pathogenic (PMID: 24552284, 24552285). This variant is present in population databases (rs780731346, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with polyarteritis nodosa or symptoms consistent with polyarteritis nodosa (PMID: 27059682, 28522451). This variant is also known as c.138/144delG. ClinVar contains an entry for this variant (Variation ID: 640066). For these reasons, this variant has been classified as Pathogenic. -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs756881285; hg19: chr22-17690423;