20-44625593-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP3_Moderate PP5_Strong

The NM_000022.4(ADA):c.454C>A(p.Leu152Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000882 in 1,587,678 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L152P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (3 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:10 U:3 O:1
• Conservation: PhyloP100: 4.72

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000022.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44625592-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 624609.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 20-44625593-G-T is Pathogenic according to our data. Variant chr20-44625593-G-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 1979.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=8, not_provided=1, Uncertain_significance=3, Pathogenic=1}. Variant chr20-44625593-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA	NM_000022.4	c.454C>A	p.Leu152Met	missense_variant	5/12	ENST00000372874.9
ADA	NM_001322051.2	c.454C>A	p.Leu152Met	missense_variant	5/11
ADA	NM_001322050.2	c.73+863C>A		intron_variant
ADA	NR_136160.2	n.546C>A		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA	ENST00000372874.9	c.454C>A	p.Leu152Met	missense_variant	5/12	1	NM_000022.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152210 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: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000157 AC: 33 AN: 209700 Hom.: 0 AF XY: 0.000195 AC XY: 22 AN XY: 112748

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: 0.000990

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.000377

GnomAD4 exome AF: 0.0000920 AC: 132 AN: 1435350 Hom.: 3 Cov.: 31 AF XY: 0.000132 AC XY: 94 AN XY: 711490

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000819

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000445 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:10 Uncertain:3 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:6 Uncertain:3 Other:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Mar 14, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.46). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001979). A different missense change at the same codon (p.Leu152Pro) has been reported to be associated with ADA-related disorder (PMID: 31031743). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Uncertain significance, flagged submission	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 152 of the ADA protein (p.Leu152Met). This variant is present in population databases (rs121908728, gnomAD 0.1%). This missense change has been observed in individual(s) with delayed onset adenosine deaminase deficiency (PMID: 9225964, 29744787). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1979). 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: 9225964). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Oct 10, 2023	The c.454C>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Leu by Met at amino acid 152. The filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.0006937 for South Asian chromosomes by gnomAD v 2.1.1, which is bigger than the ClinGen SCID VCEP threshold (0.0001742). So, PM2 is not met. The variant has been reported to segregate with SCID in 02 affected members (proband +1) from one family. LOD score: 0.6 = PP1_supporting. At least one patient (P6, PMID: 29744787) with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met: 0.5 points, * Reduced ADA enzyme activity in patient cells (see table 2) 1 point, and * Lymphocyte count partially corrected by ADA enzyme replacement therapy: 1 point = TOTAL: 2.5 points, which is highly specific for SCID (PP4_moderate, PMID: 29744787.) In summary, this variant meets the criteria to be classified as VUS for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP1_Supporting, PP4_Moderate (SCID VCEP specifications version 1.0). -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kariminejad - Najmabadi Pathology & Genetics Center	Jul 10, 2021	- -

Partial adenosine deaminase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1997

- -

Severe combined immunodeficiency disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 24, 2022

Variant summary: ADA c.454C>A (p.Leu152Met) results in a conservative amino acid change located in the Adenosine/AMP deaminase domain (IPR001365) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 209700 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency Syndrome (0.00016 vs 0.0016), allowing no conclusion about variant significance. c.454C>A has been reported in the literature in individuals affected with late-onset adenosine deaminase (ADA) deficiency (Cagdas_2018) and in a healthy homozygous individual with partial ADA deficiency (Hirschhorn 1997). These data indicate that the variant is likely to be associated with disease. Several publications report that ADA enzymatic activity could not be detected in the red cells with the variant (Hirschhorn_1997, Cagdas_2018). Eight 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 (pathogenic/likely pathogenic n=6, VUS n=2). 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.90		Gain of MoRF binding (P = 0.0678);Gain of MoRF binding (P = 0.0678);
MVP		0.86
MPC		0.62
ClinPred		0.54	D
GERP RS		3.5
Varity_R		0.93
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908728; hg19: chr20-43254234;