20-44621032-CCTCTT-C

Position:

chr20-44621032-CCTCTT-C

Variant summary

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

The NM_000022.4(ADA):c.956_960del(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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.65

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:

Genome browser will be placed here

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 20-44621032-CCTCTT-C is Pathogenic according to our data. Variant chr20-44621032-CCTCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 193544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADA	NM_000022.4 linkuse as main transcript	c.956_960del	p.Glu319GlyfsTer3	frameshift_variant	10/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322050.2 linkuse as main transcript	c.551_555del	p.Glu184GlyfsTer3	frameshift_variant	9/11		NP_001308979.1
ADA	NM_001322051.2 linkuse as main transcript	c.884_888del	p.Glu295GlyfsTer3	frameshift_variant	9/11		NP_001308980.1
ADA	NR_136160.2 linkuse as main transcript	n.983_987del		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.956_960del	p.Glu319GlyfsTer3	frameshift_variant	10/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152126

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251496

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135922

show subpopulations

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 SAS 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.:

AF XY:

0.000191

AC XY:

139

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000238

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74432

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:

0.0000943

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000565

Hom.:

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

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:10

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 30, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 29, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 31, 2016	- -
Pathogenic, no assertion criteria provided	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	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 proteinâ€™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). -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 26, 2020	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.Glu319Glyfs3. 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.Glu319Glyfs3 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2023	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, 32888943, 26022996, 23280131, 8401541, 27484032, 8227344, 28487086, 8242080, 31858364, 32307643, 27129325, 31589614, 26255240) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	ADA: PVS1, PM2, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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