NM_000022.4:c.956_960delAAGAG

Variant names:

• chr20-44621032-CCTCTT-C
• rs771266745
• NM_000022.4:c.956_960delAAGAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000022.4(ADA):​c.956_960delAAGAG​(p.Glu319GlyfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ADA NM_000022.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.65
• Publications: 7 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 20-44621032-CCTCTT-C is Pathogenic according to our data. Variant chr20-44621032-CCTCTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 193544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.956_960delAAGAG	p.Glu319GlyfsTer3	frameshift	Exon 10 of 12	NP_000013.2
	ADA	NM_001322051.2		c.884_888delAAGAG	p.Glu295GlyfsTer3	frameshift	Exon 9 of 11	NP_001308980.1
	ADA	NM_001322050.2		c.551_555delAAGAG	p.Glu184GlyfsTer3	frameshift	Exon 9 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.956_960delAAGAG	p.Glu319GlyfsTer3	frameshift	Exon 10 of 12	ENSP00000361965.4
	ADA	ENST00000537820.2	TSL:1	c.884_888delAAGAG	p.Glu295GlyfsTer3	frameshift	Exon 9 of 11	ENSP00000441818.1
	ADA	ENST00000695995.1		c.566_570delAAGAG	p.Glu189GlyfsTer3	frameshift	Exon 7 of 9	ENSP00000512318.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152126 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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251496 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 281 AN: 1461844 Hom.: 0 AF XY: 0.000191 AC XY: 139 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000238 AC: 265 AN: 1111994

Other (OTH) AF: 0.000215 AC: 13 AN: 60396

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000831

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

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:10

Feb 20, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 31, 2016

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.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 05, 2025

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.Glu319Glyfs*3) 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 (rs771266745, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 8401541, 27484032). This variant is also known as del nt1050-54. ClinVar contains an entry for this variant (Variation ID: 193544). For these reasons, this variant has been classified as Pathogenic.

Apr 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 16, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ADA c.956_960delAAGAG (p.Glu319Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent ADA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 16/121412 control chromosomes at a frequency of 0.0001318, which does not exceed the estimated maximal expected allele frequency of a pathogenic ADA variant (0.001633). This variant has been reported in multiple SCID patients in homozgyous or compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 16, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

This heterozygous p.Glu319GlyfsTer3 variant in ADA was identified by our study in an individual with severe combined immunodeficiency due to adenosine deaminase deficiency in the compound heterozygous state along with a likely pathogenic structural variant. The variant has been reported in at least 9 individuals with severe combined immunodeficiency due to adenosine deaminase deficiency ( PMID: 26376800, 23260757, 26255240) and with 0.02% (30/129198) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs771266745). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. The variant has also been reported in ClinVar as pathogenic by Integrated Genetics/Laboratory Corporation of America, EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, and GeneDx and as likely pathogenic by Counsyl (Variation ID#: 193544). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 319 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ADA gene is an established disease mechanism in autosomal recessive severe combined immunodeficiency. The presence of this variant in at least 2 affected homozygotes and in combination with a likely pathogenic variant, and in 3 individuals with severe combined immunodeficiency increases the likelihood that p.Glu319GlyfsTer3 is pathogenic (PMID:26376800). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive severe combined immunodeficiency. ACMG/AMP Criteria applied: PVS1, PM3_strong (Richards 2015).

Feb 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:4

Sep 24, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADA: PVS1, PM2, PP4

Jun 26, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ADA gene demonstrated a 5 base pair deletion in exon 10, c.956_960del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 2 amino acids downstream of the mutation, p.Glu319Glyfs*3. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ADA protein with potentially abnormal function. The p.Glu319Glyfs*3 change has been reported in the gnomAD database with a frequency of 0.023% in the European sub-population (dbSNP rs912804754). This pathogenic sequence change has previously been described in the homozygous or compound heterozygous state in patients with ADA-related severe combined immunodeficiency (SCID) (PMIDs: 26255240, 8401541, 29744787).

Jun 29, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23260757, 29744787, 35482138, 32888943, 26022996, 23280131, 27484032, 8227344, 28487086, 8242080, 31858364, 32307643, 27129325, 31589614, 26255240, 8401541, 39483481, 38676811, 37302792)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771266745; hg19: chr20-43249673;