rs780014431

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000022.4(ADA):c.424C>T(p.Arg142Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,585,090 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ADA
NM_000022.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.54

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-44625623-G-A is Pathogenic according to our data. Variant chr20-44625623-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 552928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44625623-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADA	NM_000022.4 linkuse as main transcript	c.424C>T	p.Arg142Ter	stop_gained	5/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2 linkuse as main transcript	c.424C>T	p.Arg142Ter	stop_gained	5/11		NP_001308980.1
ADA	NM_001322050.2 linkuse as main transcript	c.73+833C>T		intron_variant			NP_001308979.1
ADA	NR_136160.2 linkuse as main transcript	n.516C>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.424C>T	p.Arg142Ter	stop_gained	5/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000198

AC:

AN:

202372

Hom.:

AF XY:

0.0000276

AC XY:

AN XY:

108654

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:

0.000117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000244

AC:

AN:

1432918

Hom.:

Cov.:

AF XY:

0.0000239

AC XY:

AN XY:

709996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000488

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000520

Gnomad4 SAS exome

AF:

0.0000731

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000210

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000295

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

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:7

Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Dec 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change creates a premature translational stop signal (p.Arg142*) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8589684, 26255240). ClinVar contains an entry for this variant (Variation ID: 552928). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 18, 2017	- -

ADA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

The ADA c.424C>T variant is predicted to result in premature protein termination (p.Arg142*). This variant has been reported in the homozygous state in multiple individuals with severe combined immunodeficiency (SCID) (Santisteban et al. 1995. PubMed ID: 8589684; Pajno et al. 2020. PubMed ID: 32307643). Functional studies have reported that this variant leads to a deletion of exon 5 (Santisteban et al. 1995. PubMed ID: 8589684; Valentine. 1998. PubMed ID: 9806422). This variant is reported in 0.012% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ADA are expected to be pathogenic. This variant is interpreted as pathogenic. -

Severe combined immunodeficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2021

Variant summary: ADA c.424C>T (p.Arg142X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One publication reports experimental evidence that this variant results in a precise 116 bp deletion of exon 5. Skipping of exon 5 caused by R142X shifts the reading frame, introducing a new TAA translation stop signal at the 10th codon (Santisteban_1995). The same study, determined ADA activity in T cells and red blood cells of a patient homozygous for the variant to be <2% of normal. The variant was absent in 227376 control chromosomes (gnomAD). c.424C>T has been reported in the literature in multiple affected individuals (example, Adams_2015, Grunebaum_2012, Santisteban_1995). These data indicate that the variant is very likely to be associated with disease. One ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.80

MutationTaster

Benign

1.0

A;A

Vest4

0.85

GERP RS

1.2

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

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