rs1555844120

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2_SupportingPM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.736C>T (p.Gln246Ter)(NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant is absent in gnomAD v4 (PM2_Supporting). One patient (U444) was found homozygous for this mutation (PMID:17185467,PM3_Supporting).Based on the above evidence, this variant can be classified as pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PVS1_Met,PM2_Supporting,PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409120239/MONDO:0007064/114

Frequency

Genomes: not found (cov: 33)

Consequence

ADA
ENST00000372874.9 stop_gained

Scores

2
5

Clinical Significance

Pathogenic reviewed by expert panel P:5U:1

Conservation

PhyloP100: 0.00400
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADANM_000022.4 linkuse as main transcriptc.736C>T p.Gln246Ter stop_gained 8/12 ENST00000372874.9 NP_000013.2
ADANM_001322051.2 linkuse as main transcriptc.664C>T p.Gln222Ter stop_gained 7/11 NP_001308980.1
ADANM_001322050.2 linkuse as main transcriptc.331C>T p.Gln111Ter stop_gained 7/11 NP_001308979.1
ADANR_136160.2 linkuse as main transcriptn.828C>T non_coding_transcript_exon_variant 8/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAENST00000372874.9 linkuse as main transcriptc.736C>T p.Gln246Ter stop_gained 8/121 NM_000022.4 ENSP00000361965 P4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5Uncertain:1
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:5Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 27, 2022- -
Pathogenic, reviewed by expert panelcurationClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGenJan 24, 2024The c.736C>T (p.Gln246Ter)(NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant is absent in gnomAD v4 (PM2_Supporting). One patient (U444) was found homozygous for this mutation (PMID: 17185467,PM3_Supporting).Based on the above evidence, this variant can be classified as pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PVS1_Met,PM2_Supporting,PM3_Supporting. -
Pathogenic, criteria provided, single submitterclinical testingCounsylFeb 14, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 14, 2021This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln246*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 549915). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 31589898). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
29
DANN
Benign
0.95
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.14
N
MutationTaster
Benign
1.0
A;A;N;N
Vest4
0.93
GERP RS
-4.1

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.

Other links and lift over

dbSNP: rs1555844120; hg19: chr20-43251514; API