chr20-44624274-T-C

Variant names:

• chr20-44624274-T-C
• rs244076
• NM_000022.4:c.534A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000022.4(ADA):​c.534A>G​(p.Val178Val) 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:10
• Conservation: PhyloP100: -0.174
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.534A>G	p.Val178Val	synonymous_variant	Exon 6 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.534A>G	p.Val178Val	synonymous_variant	Exon 6 of 11		NP_001308980.1
ADA	NM_001322050.2	c.129A>G	p.Val43Val	synonymous_variant	Exon 5 of 11		NP_001308979.1
ADA	NR_136160.2	n.626A>G		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.534A>G	p.Val178Val	synonymous_variant	Exon 6 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000696038.1	n.*280A>G		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*280A>G		3_prime_UTR_variant	Exon 6 of 9			ENSP00000512344.1
ADA	ENST00000695995.1	c.217-1196A>G		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-1344A>G		intron_variant	Intron 3 of 7			ENSP00000512314.1

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

GnomAD2 exomes AF: 0.198 AC: 49698 AN: 251228 AF XY: 0.197

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 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

African (AFR) AF: 0.425 AC: 14244 AN: 33476

American (AMR) AF: 0.196 AC: 8776 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4815 AN: 26126

East Asian (EAS) AF: 0.120 AC: 4743 AN: 39682

South Asian (SAS) AF: 0.245 AC: 21112 AN: 86244

European-Finnish (FIN) AF: 0.156 AC: 8309 AN: 53394

Middle Eastern (MID) AF: 0.225 AC: 1296 AN: 5750

European-Non Finnish (NFE) AF: 0.172 AC: 190941 AN: 1111842

Other (OTH) AF: 0.201 AC: 12112 AN: 60388

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

African (AFR) AF: 0.414 AC: 17148 AN: 41430

American (AMR) AF: 0.207 AC: 3164 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3472

East Asian (EAS) AF: 0.142 AC: 734 AN: 5160

South Asian (SAS) AF: 0.250 AC: 1205 AN: 4822

European-Finnish (FIN) AF: 0.151 AC: 1603 AN: 10610

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11595 AN: 67952

Other (OTH) AF: 0.237 AC: 500 AN: 2112

Alfa AF: 0.192 Hom.: 12277

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:10

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.9
DANN	Benign	0.78
PhyloP100		-0.17
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

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