rs244076

chr20-44624274-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000022.4(ADA):c.534A>G(p.Val178=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,613,656 control chromosomes in the GnomAD database, including 31,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5350 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25828 hom.)
• Consequence: ADA NM_000022.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.174

Genes affected

ADA (HGNC:186): (adenosine deaminase) This gene encodes an enzyme that catalyzes the hydrolysis of adenosine to inosine in the purine catabolic pathway. Various mutations have been described for this gene and have been linked to human diseases related to impaired immune function such as severe combined immunodeficiency disease (SCID) which is the result of a deficiency in the ADA enzyme. In ADA-deficient individuals there is a marked depletion of T, B, and NK lymphocytes, and consequently, a lack of both humoral and cellular immunity. Conversely, elevated levels of this enzyme are associated with congenital hemolytic anemia. [provided by RefSeq, Sep 2019]

PKIG (HGNC:9019): (cAMP-dependent protein kinase inhibitor gamma) This gene encodes a member of the protein kinase inhibitor family. Studies of a similar protein in mice suggest that this protein acts as a potent competitive cAMP-dependent protein kinase inhibitor, and is a predominant form of inhibitor in various tissues. The encoded protein may be involved in osteogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 20-44624274-T-C is Benign according to our data. Variant chr20-44624274-T-C is described in ClinVar as [Benign]. Clinvar id is 254716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.174 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA	NM_000022.4	c.534A>G	p.Val178=	synonymous_variant	6/12	ENST00000372874.9
ADA	NM_001322051.2	c.534A>G	p.Val178=	synonymous_variant	6/11
ADA	NM_001322050.2	c.129A>G	p.Val43=	synonymous_variant	5/11
ADA	NR_136160.2	n.626A>G		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA	ENST00000372874.9	c.534A>G	p.Val178=	synonymous_variant	6/12	1	NM_000022.4	P4

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36686 AN: 151924 Hom.: 5325 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.198 AC: 49698 AN: 251228 Hom.: 5482 AF XY: 0.197 AC XY: 26806 AN XY: 135804

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.244

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.182 AC: 266348 AN: 1461614 Hom.: 25828 Cov.: 32 AF XY: 0.184 AC XY: 133486 AN XY: 727106

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.201

GnomAD4 genome AF: 0.242 AC: 36759 AN: 152042 Hom.: 5350 Cov.: 32 AF XY: 0.240 AC XY: 17859 AN XY: 74324

Gnomad4 AFR AF: 0.414

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.237

Alfa AF: 0.186 Hom.: 5112

Bravo AF: 0.253

Asia WGS AF: 0.231 AC: 802 AN: 3478

EpiCase AF: 0.177

EpiControl AF: 0.180

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, silent variant not near splice -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	7.9
Dann	Benign	0.78

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: rs244076; hg19: chr20-43252915; COSMIC: COSV65740435; COSMIC: COSV65740435;