rs11555566

chr20-44626579-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000022.4(ADA):c.239A>G(p.Lys80Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 1,614,086 control chromosomes in the GnomAD database, including 3,190 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• 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:9
• 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000022.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0049925745).
• BP6: Variant 20-44626579-T-C is Benign according to our data. Variant chr20-44626579-T-C is described in ClinVar as [Benign]. Clinvar id is 1954.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr20-44626579-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA	NM_000022.4	c.239A>G	p.Lys80Arg	missense_variant	4/12	ENST00000372874.9
ADA	NM_001322051.2	c.239A>G	p.Lys80Arg	missense_variant	4/11
ADA	NM_001322050.2	c.-51A>G		5_prime_UTR_variant	4/11
ADA	NR_136160.2	n.331A>G		non_coding_transcript_exon_variant	4/11

Ensembl

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

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:9

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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 12, 2011	- -
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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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;.
MutationTaster	Benign	1.0	D;D
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;