20-44624275-AC-A

Variant names:

• chr20-44624275-AC-A
• rs886041796
• NM_000022.4:c.532delG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM3_Supporting PP4 PVS1 PM2_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
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.30
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.532delG	p.Val178fs	frameshift	Exon 6 of 12	NP_000013.2
	ADA	NM_001322051.2		c.532delG	p.Val178fs	frameshift	Exon 6 of 11	NP_001308980.1
	ADA	NM_001322050.2		c.127delG	p.Val43fs	frameshift	Exon 5 of 11	NP_001308979.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.532delG	p.Val178fs	frameshift	Exon 6 of 12	ENSP00000361965.4
	ADA	ENST00000537820.2	TSL:1	c.532delG	p.Val178fs	frameshift	Exon 6 of 11	ENSP00000441818.1
	ADA	ENST00000696038.1		n.*278delG		non_coding_transcript_exon	Exon 6 of 9	ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251362 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

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:7

Apr 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 20, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Oct 10, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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).

Nov 13, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ADA-related conditions. ClinVar contains an entry for this variant (Variation ID: 505549). For these reasons, this variant has been classified as Pathogenic.

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

ADA-related disorder Pathogenic:1

May 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 03, 2021

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.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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041796; hg19: chr20-43252916;