rs121908734

Variant names:

• chr20-44624212-T-C
• rs121908734
• NM_000022.4:c.596A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-44624212-T-C
• chr20-44624212-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000022.4:c.596A>G is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 199 (p.Gln199Arg). The highest population minor allele frequency in gnomAD v4 is 0.00001440 (1/69426 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409120756/MONDO:0007064/114

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 1.58
• Publications: 7 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

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.596A>G	p.Gln199Arg	missense	Exon 6 of 12	NP_000013.2
	ADA	NM_001322051.2		c.596A>G	p.Gln199Arg	missense	Exon 6 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.191A>G	p.Gln64Arg	missense	Exon 5 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.596A>G	p.Gln199Arg	missense	Exon 6 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.596A>G	p.Gln199Arg	missense	Exon 6 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.217-1134A>G		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246770 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460016 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726144

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111176

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.49	N
PhyloP100		1.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.28
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.032
MutPred		0.60		Gain of MoRF binding (P = 0.0222)
MVP		0.75
MPC		0.15
ClinPred		0.025	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.44
Mutation Taster		=73/27	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: rs121908734; hg19: chr20-43252853;