rs11555566

Positions:

chr20-44626579-T-C

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_000022.4:c.239A>G variant in ADA is a missense variant predicted to cause substitution of lysine by arginine at amino acid 80 (p.Lys80Arg). The Popmax filtering allele frequency of this variant in the gnomAD v2.1.1 database is 0.06430, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 (BA1). This variant has been observed in 551 homozygous individuals with no feature of SCID, 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. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251993/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.059 ( 274 hom., cov: 32)

Exomes 𝑓: 0.060 ( 2916 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: 3.06

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:

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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
ADA	NM_000022.4 linkuse as main transcript	c.239A>G	p.Lys80Arg	missense_variant	4/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2 linkuse as main transcript	c.239A>G	p.Lys80Arg	missense_variant	4/11		NP_001308980.1
ADA	NM_001322050.2 linkuse as main transcript	c.-51A>G		5_prime_UTR_variant	4/11		NP_001308979.1
ADA	NR_136160.2 linkuse as main transcript	n.331A>G		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.239A>G	p.Lys80Arg	missense_variant	4/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes

AF:

0.0587

AC:

8925

AN:

152170

Hom.:

274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0656

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0476

Gnomad ASJ

AF:

0.0844

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0584

Gnomad FIN

AF:

0.0355

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0634

Gnomad OTH

AF:

0.0636

GnomAD3 exomes

AF:

0.0574

AC:

14437

AN:

251426

Hom.:

496

AF XY:

0.0587

AC XY:

7973

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0640

Gnomad AMR exome

AF:

0.0601

Gnomad ASJ exome

AF:

0.0827

Gnomad EAS exome

AF:

0.00142

Gnomad SAS exome

AF:

0.0583

Gnomad FIN exome

AF:

0.0381

Gnomad NFE exome

AF:

0.0655

Gnomad OTH exome

AF:

0.0642

GnomAD4 exome

AF:

0.0602

AC:

87946

AN:

1461798

Hom.:

2916

Cov.:

AF XY:

0.0605

AC XY:

44028

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0700

Gnomad4 AMR exome

AF:

0.0593

Gnomad4 ASJ exome

AF:

0.0805

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.0591

Gnomad4 FIN exome

AF:

0.0421

Gnomad4 NFE exome

AF:

0.0619

Gnomad4 OTH exome

AF:

0.0653

GnomAD4 genome

AF:

0.0586

AC:

8928

AN:

152288

Hom.:

274

Cov.:

AF XY:

0.0571

AC XY:

4251

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0656

Gnomad4 AMR

AF:

0.0476

Gnomad4 ASJ

AF:

0.0844

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0585

Gnomad4 FIN

AF:

0.0355

Gnomad4 NFE

AF:

0.0634

Gnomad4 OTH

AF:

0.0634

Alfa

AF:

0.0637

Hom.:

529

Bravo

AF:

0.0608

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0631

AC:

243

ESP6500AA

AF:

0.0681

AC:

300

ESP6500EA

AF:

0.0635

AC:

546

ExAC

AF:

0.0588

AC:

7145

Asia WGS

AF:

0.0380

AC:

130

AN:

3478

EpiCase

AF:

0.0682

EpiControl

AF:

0.0692

ClinVar

Significance: Benign

Submissions summary: Uncertain: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

Uncertain:1Benign:5

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 12, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	The NM_000022.4:c.239A>G variant in ADA is a missense variant predicted to cause substitution of lysine by arginine at amino acid 80 (p.Lys80Arg). The Popmax filtering allele frequency of this variant in the gnomAD v2.1.1 database is 0.06430, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 (BA1). This variant has been observed in 551 homozygous individuals with no feature of SCID, 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. (VCEP specifications version 1). -

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: Previously identified in SCID cell line in cis with L304R (Valerio 1986, PMID 3007108). However, a cell line with normal ADA activity was found to be homozygous for the L80R variant and functional assays suggested that the L304R variant was responsible for ADA inactivation. This variant has also been identified in unaffected individuals (Bell 2011 21228398). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.66

D;D

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.21

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.36

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0010

B;.

Vest4

0.16

MPC

0.12

ClinPred

0.012

GERP RS

2.6

Varity_R

0.073

gMVP

0.54

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