20-44651586-C-T

Position:

chr20-44651586-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS2_Supporting

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

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:10

Conservation

PhyloP100: -0.538

Variant links:

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 links:

ADA (HGNC:):

ADA links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ADA	NM_000022.4 linkuse as main transcript	c.22G>A	p.Asp8Asn	missense_variant	1/12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 linkuse as main transcript	c.22G>A	p.Asp8Asn	missense_variant	1/11		NP_001308980.1	F5GWI4
ADA	NM_001322050.2 linkuse as main transcript	c.-268G>A		5_prime_UTR_variant	1/11		NP_001308979.1
ADA	NR_136160.2 linkuse as main transcript	n.114G>A		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.22G>A	p.Asp8Asn	missense_variant	1/12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000695995.1 linkuse as main transcript	c.22G>A	p.Asp8Asn	missense_variant	1/9			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 linkuse as main transcript	c.22G>A	p.Asp8Asn	missense_variant	1/8			ENSP00000512314.1	A0A0S2Z3B9
ADA	ENST00000696038.1 linkuse as main transcript	n.22G>A		non_coding_transcript_exon_variant	1/9			ENSP00000512344.1	A0A8Q3SJ57

Frequencies

GnomAD3 genomes

AF:

0.0452

AC:

6871

AN:

151866

Hom.:

246

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0621

AC:

8711

AN:

140254

Hom.:

383

AF XY:

0.0691

AC XY:

5367

AN XY:

77720

show subpopulations

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 SAS exome

AF:

0.130

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.:

AF XY:

0.0602

AC XY:

41370

AN XY:

686784

show subpopulations

Gnomad4 AFR exome

AF:

0.00952

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.0937

Gnomad4 EAS exome

AF:

0.0401

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.0670

Gnomad4 NFE exome

AF:

0.0532

Gnomad4 OTH exome

AF:

0.0637

GnomAD4 genome

AF:

0.0452

AC:

6862

AN:

151974

Hom.:

244

Cov.:

AF XY:

0.0462

AC XY:

3430

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.0346

Gnomad4 ASJ

AF:

0.0931

Gnomad4 EAS

AF:

0.0542

Gnomad4 SAS

AF:

0.127

Gnomad4 FIN

AF:

0.0608

Gnomad4 NFE

AF:

0.0568

Gnomad4 OTH

AF:

0.0545

Alfa

AF:

0.0567

Hom.:

Bravo

AF:

0.0400

TwinsUK

AF:

0.0512

AC:

190

ALSPAC

AF:

0.0566

AC:

218

ESP6500AA

AF:

0.00717

AC:

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:1Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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

Benign:7

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Oct 10, 2023	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). -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 24, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29191167, 16221767, 20414589, 22952909, 18794722, 11354825, 24896148, 21734253, 17287605, 20174870, 8031011) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Adenosine deaminase 2 allozyme

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2001

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.60

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

-0.91

N;.

PrimateAI

Benign

0.43

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

GERP RS

-1.4

Varity_R

0.44

gMVP

0.44

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over