rs11555566

Variant names:

• chr20-44626579-T-C
• rs11555566
• NM_000022.4:c.239A>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BS2_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
• Clinical Significance: Benign reviewed by expert panel U:1 B:10
• Conservation: PhyloP100: 3.06

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]

ACMG classification

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 rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.239A>G	p.Lys80Arg	missense_variant	Exon 4 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.239A>G	p.Lys80Arg	missense_variant	Exon 4 of 11		NP_001308980.1
ADA	NM_001322050.2	c.-51A>G		5_prime_UTR_variant	Exon 4 of 11		NP_001308979.1
ADA	NR_136160.2	n.331A>G		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.239A>G	p.Lys80Arg	missense_variant	Exon 4 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.216+2470A>G		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.216+2470A>G		intron_variant	Intron 3 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.237A>G		non_coding_transcript_exon_variant	Exon 4 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8925 AN: 152170 Hom.: 274 Cov.: 32

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

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.: 32 AF XY: 0.0605 AC XY: 44028 AN XY: 727200

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.: 32 AF XY: 0.0571 AC XY: 4251 AN XY: 74468

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: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 Uncertain:1 Benign:5

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2011

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

- -

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. -

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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

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: 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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.66	D;D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.21	N;.
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs11555566; hg19: chr20-43255220; COSMIC: COSV65739876; COSMIC: COSV65739876;