rs778809577

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000022.4(ADA):c.703C>T(p.Arg235Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 2.39

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:

PKIG (HGNC:9019): (cAMP-dependent protein kinase inhibitor gamma) This gene encodes a member of the protein kinase inhibitor family. Studies of a similar protein in mice suggest that this protein acts as a potent competitive cAMP-dependent protein kinase inhibitor, and is a predominant form of inhibitor in various tissues. The encoded protein may be involved in osteogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PKIG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 4) in uniprot entity ADA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000022.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-44622905-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 20-44622906-G-A is Pathogenic according to our data. Variant chr20-44622906-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468281.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADA	NM_000022.4 linkuse as main transcript	c.703C>T	p.Arg235Trp	missense_variant	8/12	ENST00000372874.9
ADA	NM_001322051.2 linkuse as main transcript	c.631C>T	p.Arg211Trp	missense_variant	7/11
ADA	NM_001322050.2 linkuse as main transcript	c.298C>T	p.Arg100Trp	missense_variant	7/11
ADA	NR_136160.2 linkuse as main transcript	n.795C>T		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.703C>T	p.Arg235Trp	missense_variant	8/12	1	NM_000022.4	P4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251496

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

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

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 235 of the ADA protein (p.Arg235Trp). This variant is present in population databases (rs778809577, gnomAD 0.007%). This missense change has been observed in individual(s) with SCID (PMID: 21624848, 26255240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 468281). 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. Experimental studies have shown that this missense change affects ADA function (PMID: 9361033). This variant disrupts the p.Arg234 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313286). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 22, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.703C>T (NM_000022.4) variant in ADA gene is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 235 (p.Arg235Trp). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/113770 observed alleles) is 0.000002920 in gnomAD v2.1.1 which is below than SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least 5 individuals with SCID. Of those individuals, 2 were compound heterozygous: Patient #6, W264X, reported by Dalal I et al. (PMID: 21624848, Pathogenic according to the SCID VCEP specifications, confirmed in trans, 1pt) and Patient #26, p.G74D, reported by Chi ZH et al. (PMID: 30290665, Likey Pathogenic according to the SCID VCEP, confirmed in trans, 1 pt). 3 individuals were homozygous for PMIDs: 26255240, 26376800, and 32307643; reaching the limit for homozygous occurrence = 1 pt). Total = 3 pts, PM3_Strong. Evaluating those 5 probands, three of them had PP4 applied at supporting level: * PMID: 30290665: 171 PID-related genes(NGS panel: 0.5pt); T-B-SCID ( SCID gene panel which ruled out alternative causes 0.5pt); SCID diagnostic (0.5pt); Total 1.5pts. * PMID: 26376800: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt. TOTAL: 1.5 pts, PP4_Met. * PMID: 26255240: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt = TOTAL: 1.5 pts = PP4_Met. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PP4, PM3_Strong, and PM5_supporting. (VCEP specifications version 1). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 12, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 30, 2021	- -

ADA-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2022

The ADA c.703C>T variant is predicted to result in the amino acid substitution p.Arg235Trp. This variant was reported in the compound heterozygous and homozygous states in patients with severe combined immunodeficiency (Dalal et al 2011. PubMed ID: 21624848; Patient 26 in Chi et al 2018. PubMed ID: 30290665; Pajno et al 2020. PubMed ID: 32307643). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-43251547-G-A). Of note, a different variant at the same amino acid (p.Arg235Gln) has also been reported in patients with ADA-related disorder (Ariga et al. 2001. PubMed ID: 11313286). Based on this evidence, we interpret that c.703C>T (p.Arg235Trp) variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.98

MVP

0.98

MPC

0.64

ClinPred

0.99

GERP RS

4.2

Varity_R

0.97

gMVP

0.97

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