chr20-44624252-C-T

Variant names:

• chr20-44624252-C-T
• rs1555844416
• NM_000022.4:c.556G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

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). Synonymous variant affecting the same amino acid position (i.e. E186E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.37

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

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: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.556G>A	p.Glu186Lys	missense_variant	Exon 6 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.556G>A	p.Glu186Lys	missense_variant	Exon 6 of 11		NP_001308980.1
ADA	NM_001322050.2	c.151G>A	p.Glu51Lys	missense_variant	Exon 5 of 11		NP_001308979.1
ADA	NR_136160.2	n.648G>A		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.556G>A	p.Glu186Lys	missense_variant	Exon 6 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-1174G>A		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-1322G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.*302G>A		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*302G>A		3_prime_UTR_variant	Exon 6 of 9			ENSP00000512344.1

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:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:1 Uncertain:2

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

- -

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

- -

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

Other links and lift over

dbSNP: rs1555844416; hg19: chr20-43252893;