20-44651586-C-T

Variant names:

• chr20-44651586-C-T
• rs73598374
• NM_000022.4:c.22G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The NM_000022.2:c.22G>A variant in ADA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 8 (p.Asp8Asn). This variant is present at an overall minor allele frequency of 0.05863 (10050/171418 alleles) with the highest population minor allele frequency of 0.1300 (3033/23322) in the South Asian population in gnomAD v2.1.1. This frequency is higher than the ClinGen SCID VCEP's threshold for BA1 (>0.00721); therefore, BA1 is met. This variant has been observed in 434 homozygous individuals in gnomAD, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA115289/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.045 (244 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2797 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:10
• Conservation: PhyloP100: -0.538
• Publications: 81 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]

ADA Gene-Disease associations (from GenCC):

• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 11		NP_001308980.1
ADA	NR_136160.2	n.114G>A		non_coding_transcript_exon_variant	Exon 1 of 11
ADA	NM_001322050.2	c.-268G>A		5_prime_UTR_variant	Exon 1 of 11		NP_001308979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 9			ENSP00000512318.1
ADA	ENST00000695991.1	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 8			ENSP00000512314.1
ADA	ENST00000696038.1	n.22G>A		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6871 AN: 151866 Hom.: 246 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.0542

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0608

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0621 AC: 8711 AN: 140254 AF XY: 0.0691

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.0258

Gnomad ASJ exome AF: 0.0945

Gnomad EAS exome AF: 0.0540

Gnomad FIN exome AF: 0.0618

Gnomad NFE exome AF: 0.0535

Gnomad OTH exome AF: 0.0600

GnomAD4 exome AF: 0.0573 AC: 79583 AN: 1388672 Hom.: 2797 Cov.: 32 AF XY: 0.0602 AC XY: 41370 AN XY: 686784

African (AFR) AF: 0.00952 AC: 296 AN: 31096

American (AMR) AF: 0.0263 AC: 979 AN: 37178

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 2347 AN: 25052

East Asian (EAS) AF: 0.0401 AC: 1439 AN: 35876

South Asian (SAS) AF: 0.130 AC: 10378 AN: 79894

European-Finnish (FIN) AF: 0.0670 AC: 2297 AN: 34260

Middle Eastern (MID) AF: 0.119 AC: 543 AN: 4546

European-Non Finnish (NFE) AF: 0.0532 AC: 57618 AN: 1082936

Other (OTH) AF: 0.0637 AC: 3686 AN: 57834

GnomAD4 genome AF: 0.0452 AC: 6862 AN: 151974 Hom.: 244 Cov.: 32 AF XY: 0.0462 AC XY: 3430 AN XY: 74290

African (AFR) AF: 0.0102 AC: 422 AN: 41478

American (AMR) AF: 0.0346 AC: 528 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 323 AN: 3468

East Asian (EAS) AF: 0.0542 AC: 279 AN: 5146

South Asian (SAS) AF: 0.127 AC: 610 AN: 4814

European-Finnish (FIN) AF: 0.0608 AC: 644 AN: 10586

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0568 AC: 3855 AN: 67892

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0556 Hom.: 82

Bravo AF: 0.0400

TwinsUK AF: 0.0512 AC: 190

ALSPAC AF: 0.0566 AC: 218

ESP6500AA AF: 0.00717 AC: 23

ESP6500EA AF: 0.0419 AC: 286

ExAC AF: 0.0343 AC: 3458

Asia WGS AF: 0.0750 AC: 261 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Benign:7

Mar 06, 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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000022.2:c.22G>A variant in ADA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 8 (p.Asp8Asn). This variant is present at an overall minor allele frequency of 0.05863 (10050/171418 alleles) with the highest population minor allele frequency of 0.1300 (3033/23322) in the South Asian population in gnomAD v2.1.1. This frequency is higher than the ClinGen SCID VCEP's threshold for BA1 (>0.00721); therefore, BA1 is met. This variant has been observed in 434 homozygous individuals in gnomAD, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0). -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

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

This variant is associated with the following publications: (PMID: 29191167, 16221767, 20414589, 22952909, 18794722, 11354825, 24896148, 21734253, 17287605, 20174870, 8031011) -

Adenosine deaminase 2 allozyme Pathogenic:1

Mar 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Benign:1

Jan 09, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.91	N;.
PhyloP100		-0.54
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.28	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.86	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.071
MPC		0.14
ClinPred		0.017	T
GERP RS		-1.4
PromoterAI		-0.013	Neutral
Varity_R		0.44
gMVP		0.44
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs73598374; hg19: chr20-43280227; COSMIC: COSV54859237; COSMIC: COSV54859237;