chr20-44620391-G-C

Variant names:

• chr20-44620391-G-C
• rs121908715
• NM_000022.4:c.986C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000022.4(ADA):​c.986C>G​(p.Ala329Gly) 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. 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. A329V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.32
• Publications: 0 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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44620391-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1959.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

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.986C>G	p.Ala329Gly	missense	Exon 11 of 12	NP_000013.2
	ADA	NM_001322051.2		c.914C>G	p.Ala305Gly	missense	Exon 10 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.581C>G	p.Ala194Gly	missense	Exon 10 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.986C>G	p.Ala329Gly	missense	Exon 11 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.914C>G	p.Ala305Gly	missense	Exon 10 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.596C>G	p.Ala199Gly	missense	Exon 8 of 9	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.3
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.90		Loss of ubiquitination at K331 (P = 0.1264)
MVP		0.92
MPC		0.59
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.81
gMVP		0.86
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908715; hg19: chr20-43249032;