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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.596A>G	p.Gln199Arg	missense_variant	Exon 6 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.596A>G	p.Gln199Arg	missense_variant	Exon 6 of 11		NP_001308980.1
ADA	NM_001322050.2	c.191A>G	p.Gln64Arg	missense_variant	Exon 5 of 11		NP_001308979.1
ADA	NR_136160.2	n.688A>G		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.596A>G	p.Gln199Arg	missense_variant	Exon 6 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000696038.1	n.*342A>G		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*342A>G		3_prime_UTR_variant	Exon 6 of 9			ENSP00000512344.1
ADA	ENST00000695995.1	c.217-1134A>G		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-1282A>G		intron_variant	Intron 3 of 7			ENSP00000512314.1

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 199 of the ADA protein (p.Gln199Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ADA-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jun 10, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.49	N;.
PhyloP100		1.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.28
Sift	Benign	0.15	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0	B;.
Vest4		0.032
MutPred		0.60		Gain of MoRF binding (P = 0.0222);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;