rs121908736

chr20-44626592-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 5P and 6B. PM1 PM2 PP3 BP4 BS1_Supporting BS2

The NM_000022.4(ADA):c.226C>T(p.Arg76Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000188 in 1,613,988 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:6 O:1
• Conservation: PhyloP100: 4.52

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 Likely_benign. Variant got -1 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, 5 uncertain in NM_000022.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, MutationAssessor, PROVEAN, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.29511517).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000775 (118/152198) while in subpopulation AFR AF= 0.00267 (111/41532). AF 95% confidence interval is 0.00227. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA	NM_000022.4	c.226C>T	p.Arg76Trp	missense_variant	4/12	ENST00000372874.9
ADA	NM_001322051.2	c.226C>T	p.Arg76Trp	missense_variant	4/11
ADA	NM_001322050.2	c.-64C>T		5_prime_UTR_variant	4/11
ADA	NR_136160.2	n.318C>T		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA	ENST00000372874.9	c.226C>T	p.Arg76Trp	missense_variant	4/12	1	NM_000022.4	P4

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000282 AC: 71 AN: 251410 Hom.: 2 AF XY: 0.000235 AC XY: 32 AN XY: 135884

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 82 AN XY: 727188

Gnomad4 AFR exome AF: 0.00329

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74400

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000888

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Uncertain:4 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 76 of the ADA protein (p.Arg76Trp). This variant is present in population databases (rs121908736, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with partial adenosine deaminase deficiency (PMID: 2166947). ClinVar contains an entry for this variant (Variation ID: 1962). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADA: PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2017	The R76W variant in the ADA gene has been reported previously in the homozygous state or with a second ADA variant in patients with adenosine deaminase deficiency (Hirschhorn et al., 1990; Hirschhorn et al., 1992; Hirschhorn et al., 1993). This is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The R76W variant is observed in 66/24028 (0.27%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.We consider it to be a variant of uncertain significance. -

Partial adenosine deaminase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.050	T;T
Polyphen		1.0	D;.
Vest4		0.92
MVP		0.96
MPC		0.64
ClinPred		0.24	T
GERP RS		3.9
Varity_R		0.78
gMVP		0.77

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: rs121908736; hg19: chr20-43255233;