rs121908740

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP1_ModeratePM5PM3

This summary comes from the ClinGen Evidence Repository: NM_000022.4:c.631C>T is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 211 (p. Arg211Cys). The highest population minor allele frequency in gnomAD v4 is 0.0005167 (31/60000) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The variant has been reported to segregate with SCID in 2 affected family members from 1 family (PP1_moderate; PMID :8051429). Patient was found heterozygous for R211C & L107P which is classified as likely pathogenic by SCID VCEP (1 pt.) (PM3) (PMID:2166947).Another missense variant [c.632G>A, p.Arg211His)] in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5).In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_moderate,PM3,PM5(VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA115285/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

ADA
ENST00000372874.9 missense

Scores

9
8
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:9U:1O:1

Conservation

PhyloP100: 5.17
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM3
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADANM_000022.4 linkuse as main transcriptc.631C>T p.Arg211Cys missense_variant 7/12 ENST00000372874.9 NP_000013.2
ADANM_001322050.2 linkuse as main transcriptc.226C>T p.Arg76Cys missense_variant 6/11 NP_001308979.1
ADANM_001322051.2 linkuse as main transcriptc.607-124C>T intron_variant NP_001308980.1
ADANR_136160.2 linkuse as main transcriptn.723C>T non_coding_transcript_exon_variant 7/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAENST00000372874.9 linkuse as main transcriptc.631C>T p.Arg211Cys missense_variant 7/121 NM_000022.4 ENSP00000361965 P4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
33
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251340
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135844
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000694
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:
0.000815
GnomAD4 exome
AF:
0.0000349
AC:
51
AN:
1461770
Hom.:
0
Cov.:
33
AF XY:
0.0000330
AC XY:
24
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000693
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74354
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000425
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.000107
AC:
13
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:1Other:1
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:7Uncertain:1Other:1
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Uncertain significance, flagged submissionclinical testingCounsylMay 10, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 01, 2018The ADA c.631C>T (p.Arg211Cys) variant was first reported by Hirschhorn et al. (1990) in a child with partial adenosine deaminase (ADA) deficiency. This patient was compound heterozygous for p.Arg211Cys and a second missense variant, and had approximately 8% residual ADA activity in lymphoid cells. The p.Arg211Cys variant was subsequently identified in a compound heterozygous state with a second deletion variant in two siblings with ADA deficiency and combined immunodeficiency, with no detectable ADA activity. The p.Arg211Cys variant was also detected in a heterozygous state in the mother, two additional siblings, and in a patient's child, all of whom had normal or below normal ADA activity (Shovlin et al. 1994). Control data are unavailable for this variant, but it is reported at a frequency of 0.00078 in the Latino population of the Exome Aggregation Consortium. Expression studies in COS cells by Jiang et al. (1997) showed that the p.Arg211Cys variant resulted in residual ADA activity of approximately 4% of normal. Another variant at this position, p.Arg211His, has also been seen in patients with ADA deficiency (Akeson et al. 1988; Arredondo-Vega et al. 1998). Based on the collective evidence, the p.Arg211Cys variant is classified as likely pathogenic for adenosine deaminase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 211 of the ADA protein (p.Arg211Cys). This variant is present in population databases (rs121908740, gnomAD 0.07%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 2166947, 8051429, 9616253). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1966). 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 not expected to disrupt ADA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 9361033, 9758612). This variant disrupts the p.Arg211 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1974554, 9414266, 9758612, 26376800). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Pathogenic, criteria provided, single submittercurationLaboratory of Medical Genetics, National & Kapodistrian University of AthensFeb 01, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 25, 2024- -
Likely pathogenic, reviewed by expert panelcurationClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGenJan 10, 2024NM_000022.4:c.631C>T is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 211 (p. Arg211Cys). The highest population minor allele frequency in gnomAD v4 is 0.0005167 (31/60000) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The variant has been reported to segregate with SCID in 2 affected family members from 1 family (PP1_moderate; PMID :8051429). Patient was found heterozygous for R211C & L107P which is classified as likely pathogenic by SCID VCEP (1 pt.) (PM3) (PMID: 2166947).Another missense variant [c.632G>A, p.Arg211His)] in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_moderate,PM3,PM5(VCEP specifications version 1). -
Partial adenosine deaminase deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 1994- -
Severe combined immunodeficiency disease Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 26, 2022Variant summary: ADA c.631C>T (p.Arg211Cys) results in a non-conservative amino acid change located in the adenosine deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251340 control chromosomes, predominantly at a frequency of 0.00069 within the Latino subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency (0.00013 vs 0.0014), allowing no conclusion about variant significance. c.631C>T has been reported in the literature as a compound heterozygous genotype in an individual with partial ADA deficiency, detected as 8% ADA activity in lymphoid cells, and in two siblings affected with late onset severe combined immunodeficiency with ADA deficiency, where the variant segregated with disease in the family (e.g. Hirschhorn_1990, Shovlin_1994). Multiple publications report evidence evaluating an impact on protein function (e.g. Hirschhorn_1990, Jiang_1997, Arredondo-Vega_1998) and experiments expressing the variant in an in vitro model system found that the variant results in <5% of normal activity. Another variant, p.Arg211His, affecting the same amino acid residue has also been observed in individuals with severe combined immunodeficiency and has been classified as pathogenic (ClinVar ID: 1957). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as either pathogenic (n=1) or likely pathogenic (n=3), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.92
D
M_CAP
Pathogenic
0.54
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-7.2
D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.014
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.87
Loss of methylation at R211 (P = 0.0329);
MVP
0.95
MPC
0.61
ClinPred
0.79
D
GERP RS
4.0
Varity_R
0.80
gMVP
0.91

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.

Other links and lift over

dbSNP: rs121908740; hg19: chr20-43251695; API