rs1555844416

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000022.4(ADA):​c.556G>A​(p.Glu186Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

ADA
NM_000022.4 missense

Scores

13
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.37
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 20-44624252-C-T is Pathogenic according to our data. Variant chr20-44624252-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556213.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADANM_000022.4 linkc.556G>A p.Glu186Lys missense_variant Exon 6 of 12 ENST00000372874.9 NP_000013.2 P00813A0A0S2Z381
ADANM_001322051.2 linkc.556G>A p.Glu186Lys missense_variant Exon 6 of 11 NP_001308980.1 F5GWI4
ADANM_001322050.2 linkc.151G>A p.Glu51Lys missense_variant Exon 5 of 11 NP_001308979.1
ADANR_136160.2 linkn.648G>A non_coding_transcript_exon_variant Exon 6 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAENST00000372874.9 linkc.556G>A p.Glu186Lys missense_variant Exon 6 of 12 1 NM_000022.4 ENSP00000361965.4 P00813
ADAENST00000695995.1 linkc.217-1174G>A intron_variant Intron 3 of 8 ENSP00000512318.1 A0A8Q3SI64
ADAENST00000695991.1 linkc.217-1322G>A intron_variant Intron 3 of 7 ENSP00000512314.1 A0A0S2Z3B9
ADAENST00000696038.1 linkn.*302G>A non_coding_transcript_exon_variant Exon 6 of 9 ENSP00000512344.1 A0A8Q3SJ57
ADAENST00000696038.1 linkn.*302G>A 3_prime_UTR_variant Exon 6 of 9 ENSP00000512344.1 A0A8Q3SJ57

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
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:1Uncertain:2
Apr 04, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 18, 2024
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 30, 2018
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
D;D
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.1
D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.017
D;D
Polyphen
1.0
D;.
Vest4
0.95
MutPred
0.90
Gain of methylation at E186 (P = 0.0071);Gain of methylation at E186 (P = 0.0071);
MVP
1.0
MPC
0.66
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.98
gMVP
0.98

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: rs1555844416; hg19: chr20-43252893; API