rs780014431

Positions:

• chr20-44625623-G-A
• chr20-44625623-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. R142R) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.54

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 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	UniProt
ADA	NM_000022.4	c.424C>T	p.Arg142Ter	stop_gained	5/12	ENST00000372874.9
ADA	NM_001322051.2	c.424C>T	p.Arg142Ter	stop_gained	5/11
ADA	NM_001322050.2	c.73+833C>T		intron_variant
ADA	NR_136160.2	n.516C>T		non_coding_transcript_exon_variant	5/11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 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: 0.00

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: 4 AN: 202372 Hom.: 0 AF XY: 0.0000276 AC XY: 3 AN XY: 108654

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: 35 AN: 1432918 Hom.: 0 Cov.: 31 AF XY: 0.0000239 AC XY: 17 AN XY: 709996

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: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

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.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

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:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, 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	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 24, 2020	- -

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	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.80	D
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

Other links and lift over

dbSNP: rs780014431; hg19: chr20-43254264;