chr20-44625593-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP4_ModeratePP1

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA115292/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 3 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:12U:3O:1

Conservation

PhyloP100: 4.72

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4 link	c.454C>A	p.Leu152Met	missense_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 link	c.454C>A	p.Leu152Met	missense_variant	Exon 5 of 11		NP_001308980.1	F5GWI4
ADA	NM_001322050.2 link	c.73+863C>A		intron_variant	Intron 4 of 10		NP_001308979.1
ADA	NR_136160.2 link	n.546C>A		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 link	c.454C>A	p.Leu152Met	missense_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000695995.1 link	c.217-2515C>A		intron_variant	Intron 3 of 8			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 link	c.217-2663C>A		intron_variant	Intron 3 of 7			ENSP00000512314.1	A0A0S2Z3B9
ADA	ENST00000696038.1 link	n.*200C>A		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000696038.1 link	n.*200C>A		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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:

AN:

209700

Hom.:

AF XY:

0.000195

AC XY:

AN XY:

112748

show subpopulations

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.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

711490

show subpopulations

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:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74490

show subpopulations

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.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:12Uncertain:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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

Pathogenic:7Uncertain:3Other:1

Oct 10, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Mar 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Sep 01, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 29, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2018

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.454C>A(p.Leu152Met) variant in ADA gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Severe Combined Immunodeficiency Syndrome / adenosine deaminase (ADA) deficiency (Cagdas D, et al., 2018; Firtina S, et al., 2020; 2020 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference., 2020). This variant has also been observed to segregate with disease in related individuals. Functional expression studies of this variant showed that it leads to less enzymatic activity. However, it was concluded that p.Leu152Met variant will result in disease in homozygous individuals challenged by severe environmental stresses, or in heterozygous individuals when combined with another null variant (Hirschhorn R, et al., 1997). The p.Leu152Met variant is present with allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on ADA gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 152 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another reportable variant in ADA gene, the molecular diagnosis is not confirmed. -

May 18, 2021

Pars Genome Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published in vitro functional studies demonstrate a damaging effect on ADA activity (PMID: 39182630, 9225964); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14499267, 34426522, 36964972, 32445296, 38374194, 39182630, 9225964, 29744787) -

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Partial adenosine deaminase deficiency

Pathogenic:1

Jul 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Severe combined immunodeficiency disease

Pathogenic:1

Mar 24, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

H;.

PrimateAI

Uncertain

0.59

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over