NM_000022.4:c.758G>T

Variant names:

• chr20-44622851-C-A
• rs148994526
• NM_000022.4:c.758G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000022.4(ADA):​c.758G>T​(p.Arg253Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253W) has been classified as Uncertain significance. The gene ADA is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 3 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

Specifications for ADA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36424464).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.758G>T	p.Arg253Leu	missense	Exon 8 of 12	NP_000013.2
	ADA	NM_001322051.2		c.686G>T	p.Arg229Leu	missense	Exon 7 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.353G>T	p.Arg118Leu	missense	Exon 7 of 11	NP_001308979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.758G>T	p.Arg253Leu	missense	Exon 8 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.686G>T	p.Arg229Leu	missense	Exon 7 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.368G>T	p.Arg123Leu	missense	Exon 5 of 9	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.059
DANN	Benign	0.96
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.039	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.10	N
PhyloP100		0.13
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.32
Sift	Benign	0.36	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.70		Loss of solvent accessibility (P = 0.1077)
MVP		0.82
MPC		0.18
ClinPred		0.11	T
GERP RS		-5.0
Varity_R		0.18
gMVP		0.68
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs148994526; hg19: chr20-43251492;