rs121908740

Positions:

• chr20-44623054-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5 PM3 PP1_Moderate

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 NM_000022.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9 U:1 O:1
• Conservation: PhyloP100: 5.17

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]

ADA (HGNC:):

ACMG classification

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
ADA	NM_000022.4	c.631C>T	p.Arg211Cys	missense_variant	7/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322050.2	c.226C>T	p.Arg76Cys	missense_variant	6/11		NP_001308979.1
ADA	NM_001322051.2	c.607-124C>T		intron_variant			NP_001308980.1
ADA	NR_136160.2	n.723C>T		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.631C>T	p.Arg211Cys	missense_variant	7/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.241C>T	p.Arg81Cys	missense_variant	4/9			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-124C>T		intron_variant				ENSP00000512314.1
ADA	ENST00000696038.1	n.*377C>T		non_coding_transcript_exon_variant	7/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*377C>T		3_prime_UTR_variant	7/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33

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

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

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

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:9 Uncertain:1 Other:1

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 Pathogenic:7 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	May 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This 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 submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 2018	The 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 10, 2024	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). -

Partial adenosine deaminase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1994

- -

Severe combined immunodeficiency disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 26, 2022

Variant 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
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

Other links and lift over

dbSNP: rs121908740; hg19: chr20-43251695;