20-44622894-C-T

Position:

• chr20-44622894-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000022.4(ADA):c.715G>A is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 239 (p.Gly239Ser). The filtering allele frequency (the upper threshold of the 95% CI of 9/44902) of the c.715G>Avariant in ADA is 0.00008198 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold 0.0001742 for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Another missense variant [c.716G>A], p.Gly239Asp] in the same codon has been classified as likely pathogenic for SCID by the ClinGen SCID VCEP (PM5_Supporting). Based on the above evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting,PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9871547/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:5
• Conservation: PhyloP100: 5.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.715G>A	p.Gly239Ser	missense_variant	8/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.643G>A	p.Gly215Ser	missense_variant	7/11		NP_001308980.1
ADA	NM_001322050.2	c.310G>A	p.Gly104Ser	missense_variant	7/11		NP_001308979.1
ADA	NR_136160.2	n.807G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.715G>A	p.Gly239Ser	missense_variant	8/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

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: 0.0000239 AC: 6 AN: 251488 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135922

Gnomad AFR exome AF: 0.00

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: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:5

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:4 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 11, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.715G>A (p.Gly239Ser) variant has been reported in two studies. It is found in one patient who was compound heterozygous for three variants including the p.Gly239Ser variant and the p.Arg34Ser variant in cis and a third variant in trans (Okura et al. 2011). The variant has also been reported in compound heterozygous state in the unaffected mother of a patient with adenosine deaminase deficiency. Functional studies using E. Coli found the p.Gly239Ser variant to have 1-2.2% ADA activity of wild type (Ariga et al. 2001, Hershfield et al. 2003, Okura et al. 2011, 6x). Western blot of E.Coli show the p.Gly239Ser variant combined with p.Arg34Ser has no expression (Okura et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00005 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence from the literature the p.Gly239Ser variant alone is considered a partial mutation, but in cis with the p.Arg34Ser variant appears to be a complex allele. The complex allele is classified as a variant of unknown significance but suspicious for pathogenicity for adenosine deaminase deficiency. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 02, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 10, 2024	NM_000022.4(ADA):c.715G>A is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 239 (p.Gly239Ser). The filtering allele frequency (the upper threshold of the 95% CI of 9/44902) of the c.715G>A variant in ADA is 0.00008198 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold 0.0001742 for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Another missense variant [c.716G>A], p.Gly239Asp] in the same codon has been classified as likely pathogenic for SCID by the ClinGen SCID VCEP (PM5_Supporting). Based on the above evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting,PM5_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 239 of the ADA protein (p.Gly239Ser). This variant is present in population databases (rs777820729, gnomAD 0.004%). This missense change has been observed in individual(s) with ADA-related conditions (PMID: 21410451). ClinVar contains an entry for this variant (Variation ID: 338506). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 11160213). This variant disrupts the p.Gly239 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26255240, 30858051). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 18, 2023

Variant summary: ADA c.715G>A (p.Gly239Ser) 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 2.4e-05 in 251488 control chromosomes. c.715G>A has been reported in the literature in a paradoxical healthy carrier mother of a SCID proband who also carried G74D in trans, while the affected proband did not carry the variant of interest (Ariga_2001). This paradoxical healthy carrier displayed ADA activity in PBMC and granulocytes at about 1% of normal, however had a normal number of lymphocytes in peripheral blood and did not display any SCID phenotype. Additionally, the variant was reported in a SCID infant who carried Q119X in trans and R34S in cis (Okura_2011). From both patient reports, functional studies were performed for the variants in isolation and in combination. In both studies, ADA activity in transfected cells was reported at <10% of wild-type in transfected cells (Ariga_2001, Okura_2011). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, classifying the variant as likely pathogenic (n=3) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.98		Gain of disorder (P = 0.1187);.;
MVP		0.97
MPC		0.62
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.96

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: rs777820729; hg19: chr20-43251535;