20-44621082-A-C

Position:

• chr20-44621082-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000022.4(ADA):​c.911T>G​(p.Leu304Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,104 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.11

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 20-44621082-A-C is Pathogenic according to our data. Variant chr20-44621082-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.911T>G	p.Leu304Arg	missense_variant	10/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.839T>G	p.Leu280Arg	missense_variant	9/11		NP_001308980.1
ADA	NM_001322050.2	c.506T>G	p.Leu169Arg	missense_variant	9/11		NP_001308979.1
ADA	NR_136160.2	n.938T>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.911T>G	p.Leu304Arg	missense_variant	10/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.521T>G	p.Leu174Arg	missense_variant	7/9			ENSP00000512318.1
ADA	ENST00000695991.1	c.449T>G	p.Leu150Arg	missense_variant	6/8			ENSP00000512314.1
ADA	ENST00000695956.1	c.65T>G	p.Leu22Arg	missense_variant	1/3			ENSP00000512285.1
ADA	ENST00000696038.1	n.*668T>G		non_coding_transcript_exon_variant	8/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*668T>G		3_prime_UTR_variant	8/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000437 AC: 11 AN: 251496 Hom.: 0 AF XY: 0.0000515 AC XY: 7 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.0000724

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 304 of the ADA protein (p.Leu304Arg). This variant is present in population databases (rs199422327, gnomAD 0.008%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 46025, 1284479, 17185467). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1006T>G. ClinVar contains an entry for this variant (Variation ID: 1958). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 3007108). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1986	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 10, 2021	NM_000022.2(ADA):c.911T>G(L304R) is a missense variant classified as likely pathogenic in the context of adenosine deaminase deficiency. L304R has been observed in cases with relevant disease (PMID: 17185467, 1346349). Functional assessments of this variant are available in the literature (PMID: 3007108). L304R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000022.2(ADA):c.911T>G(L304R) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

ADA-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

The ADA c.911T>G variant is predicted to result in the amino acid substitution p.Leu304Arg. This variant has been reported in an individual with adenosine deaminase deficiency; however, a second pathogenic variant was not identified (Valerio et al. 1986. PubMed ID: 3007108). It has been reported in the compound heterozygous state in individuals with adenosine deaminase deficiency (Table S7, Bell et al. 2011. PubMed ID: 21228398; Rojas-Restrepo et al. 2021. PubMed ID: 34975878). In vitro and in situ functional studies demonstrate this variant alters restriction sites, reduces hydrophobic properties, and produces a protein lacking catalytic activity (Valerio et al. 1986. PubMed ID: 3007108; Rojas-Restrepo et al. 2021. PubMed ID: 34975878). This variant is reported in 0.0097% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 19, 2024

PP3, PM1, PM2, PM3, PS3_supporting, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.97		Loss of stability (P = 0.0053);.;
MVP		0.98
MPC		0.76
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.99

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: rs199422327; hg19: chr20-43249723;