chr20-44625622-C-T

Position:

• chr20-44625622-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1).This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA266009/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:11 O:1
• Conservation: PhyloP100: 1.47

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.425G>A	p.Arg142Gln	missense_variant	5/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.425G>A	p.Arg142Gln	missense_variant	5/11		NP_001308980.1
ADA	NM_001322050.2	c.73+834G>A		intron_variant			NP_001308979.1
ADA	NR_136160.2	n.517G>A		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.425G>A	p.Arg142Gln	missense_variant	5/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-2544G>A		intron_variant				ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2692G>A		intron_variant				ENSP00000512314.1
ADA	ENST00000696038.1	n.*171G>A		non_coding_transcript_exon_variant	5/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*171G>A		3_prime_UTR_variant	5/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152188 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00101 AC: 204 AN: 202328 Hom.: 2 AF XY: 0.000681 AC XY: 74 AN XY: 108662

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000643

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000690

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000431 AC: 617 AN: 1432964 Hom.: 2 Cov.: 31 AF XY: 0.000375 AC XY: 266 AN XY: 710034

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.000781

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000765

Gnomad4 OTH exome AF: 0.000979

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152306 Hom.: 4 Cov.: 32 AF XY: 0.00359 AC XY: 267 AN XY: 74462

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0223 Hom.: 2349

Bravo AF: 0.00440

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00119 AC: 143

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:11 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 Uncertain:1 Benign:6 Other:1

Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 10, 2024	NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1). This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ADA NM_000022.3 exon 5 p.Arg142Gln (c.425G>A): This variant has been reported in the literature in one individual, the unaffected father of a proband with Severe Combined Immunodeficiency (SCID). This variant was not identified in the affected proband, and this proband was reported to carry a different homozygous nonsense mutation (Santisteban 1995 PMID:8589684). This variant is present in 1.3% (276/20894) of African alleles including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-43254263-C-T). This variant is present in ClinVar (Variation ID: 68262). This variant amino acid Glutamine (Gln) is present in 9 species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest a reduction in ADA activity vs. wild type with literature suggesting this may be a "partial" variant; however, these studies may not accurately represent in vivo biological function (Santisteban 1995 PMID:8589684, Arredondo-Vega 1998 PMID:9758612).In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2018	The R142Q variant in the ADA gene has been reported previously, along with another variant, in the unaffected father of a Somali child with SCID who was homozygous for a nonsense variant in the ADA gene (Santisteban et al., 1995). The R142Q variant is observed in 265/19952 (1.3%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016). The R142Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In vitro function studies showed the R142Q variant reduced ADA enzyme activity between 42.8-80% compared to wild type (Richard et al., 2002; Santisteban et al., 1995). We interpret R142Q as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 03, 2022

Variant summary: ADA c.425G>A (p.Arg142Gln) results in a conservative amino acid change located in the Adenosine deaminase domain (IPR001365) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 202328 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADA causing Severe Combined Immunodeficiency phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.425G>A has been reported in the literature in an unaffected compound heterozygous (Q3X/R142Q) individual with an affected child who was homozygous for Q3X (Santisteban_1995). Two studies have demonstrated this variant partially reduce enzyme activity in vitro (Santisteban_1995 and Arredono-Vega_1998). Additionally, Richard_2000 demonstrated that recombinant human ADA bearing the R142Q mutation impaired binding to a CD26+ ADA-deficient human T cell line. These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=4), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

ADA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.25
Sift	Benign	0.47	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.024	B;.
Vest4		0.39
MVP		0.84
MPC		0.17
ClinPred		0.015	T
GERP RS		-0.31
Varity_R		0.087
gMVP		0.43

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: rs61732239; hg19: chr20-43254263; COSMIC: COSV65740449; COSMIC: COSV65740449;