rs886041796

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PP4PM2_SupportingPM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000022.4:c.532del (p.Val178*) variant in ADA creates a premature translational stop signal in exon 6 (of 12) and is expected to result in nonsense-mediated decay in a loss of function gene (PVS1). This variant was reported as homozygous in an infant with T-B- severe combined immunodeficiency (SCID) (PMID:30290665) (PP4, PM3_Supporting). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.0001 (2/19948 alleles) in the East Asian population, which is lower than the ADA cutoff (gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PP4, PM3_Supporting, PM2_Supporting (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA636174167/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ADA
NM_000022.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 7.30

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:

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]

PKIG links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

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

PM2

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

PM3

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/exons	MANE	Protein
ADA	NM_000022.4 linkuse as main transcript	c.532del	p.Val178Ter	frameshift_variant	6/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2 linkuse as main transcript	c.532del	p.Val178Ter	frameshift_variant	6/11		NP_001308980.1
ADA	NM_001322050.2 linkuse as main transcript	c.127del	p.Val43Ter	frameshift_variant	5/11		NP_001308979.1
ADA	NR_136160.2 linkuse as main transcript	n.624del		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.532del	p.Val178Ter	frameshift_variant	6/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes

AF:

0.00000657

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:

0.000193

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:

0.00000398

AC:

AN:

251362

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

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:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

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:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Oct 10, 2023	The NM_000022.4:c.532del (p.Val178*) variant in ADA creates a premature translational stop signal in exon 6 (of 12) and is expected to result in nonsense-mediated decay in a loss of function gene (PVS1). This variant was reported as homozygous in an infant with T-B- severe combined immunodeficiency (SCID) (PMID: 30290665) (PP4, PM3_Supporting). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.0001 (2/19948 alleles) in the East Asian population, which is lower than the ADA cutoff (gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PP4, PM3_Supporting, PM2_Supporting (SCID VCEP specifications version 1.0). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 06, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2017	The p.Val178X variant in ADA has not been previously reported in individuals wit h adenosine deaminase (ADA) deficiency, but was identified in 2/18938 East Asian individuals by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/). This variant is a deletion of 1 nucleotide at position 532, which g enerates a premature termination codon at amino acid position 178. Loss of funct ion of the ADA gene is an established disease mechanism in severe combined immun odeficiency due to adenosine deaminase deficiency. In summary, although addition al studies are required to fully establish its clinical significance, the p.Val1 78X variant is likely pathogenic due to its predicted impact to the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 505549). This variant has not been reported in the literature in individuals affected with ADA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Val178*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 13, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 20, 2017	- -

ADA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2024

The ADA c.532delG variant is predicted to result in premature protein termination (p.Val178*). This variant has been reported in the homozygous state in an individual with severe combined immunodeficiency (case #51, Chi et al. 2018. PubMed ID: 30290665). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as pathogenic by the ClinGen Severe Combined Immunodeficiency Variant Expert Panel (VCEP, https://www.ncbi.nlm.nih.gov/clinvar/variation/505549/). Protein truncating variants in ADA are expected to be pathogenic. This variant is interpreted as pathogenic -

Severe combined immunodeficiency disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 03, 2021

Variant summary: ADA c.532delG (p.Val178X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251362 control chromosomes. c.532delG has been reported in the literature in a homozygous individual affected with Severe Combined Immunodeficiency (Chi_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=2) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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