rs121908728

Variant names:

• chr20-44625593-G-T
• rs121908728
• NM_000022.4:c.454C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-44625593-G-T
• chr20-44625593-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.454C>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Leu by Met at amino acid 152.The filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.0006937 for South Asian chromosomes by gnomAD v 2.1.1, which is bigger than the ClinGen SCID VCEP threshold (0.0001742). So, PM2 is not met.The variant has been reported to segregate with SCID in 02 affected members (proband +1) from one family. LOD score: 0.6 = PP1_supporting.At least one patient (P6, PMID:29744787) with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met: 0.5 points, * Reduced ADA enzyme activity in patient cells (see table 2) 1 point, and * Lymphocyte count partially corrected by ADA enzyme replacement therapy: 1 point = TOTAL: 2.5 points, which is highly specific for SCID (PP4_moderate, PMID:29744787.)In summary, this variant meets the criteria to be classified as VUS for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP1_Supporting, PP4_Moderate (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA115292/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (3 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:13 U:3 O:1
• Conservation: PhyloP100: 4.72
• Publications: 5 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]

ADA Gene-Disease associations (from GenCC):

• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 3 ACMG points.

• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.454C>A	p.Leu152Met	missense	Exon 5 of 12	NP_000013.2
	ADA	NM_001322051.2		c.454C>A	p.Leu152Met	missense	Exon 5 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.73+863C>A		intron	N/A	NP_001308979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.454C>A	p.Leu152Met	missense	Exon 5 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.454C>A	p.Leu152Met	missense	Exon 5 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.217-2515C>A		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000157 AC: 33 AN: 209700 AF XY: 0.000195

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: 0.0000547

Gnomad OTH exome AF: 0.000377

GnomAD4 exome AF: 0.0000920 AC: 132 AN: 1435350 Hom.: 3 Cov.: 31 AF XY: 0.000132 AC XY: 94 AN XY: 711490

African (AFR) AF: 0.00 AC: 0 AN: 33076

American (AMR) AF: 0.00 AC: 0 AN: 41298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38622

South Asian (SAS) AF: 0.00137 AC: 113 AN: 82364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51294

Middle Eastern (MID) AF: 0.000637 AC: 3 AN: 4710

European-Non Finnish (NFE) AF: 0.00000819 AC: 9 AN: 1099184

Other (OTH) AF: 0.000101 AC: 6 AN: 59318

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000347 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	3	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (12)
3	-	-	not provided (3)
1	-	-	Partial adenosine deaminase deficiency (1)
1	-	-	Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		4.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.90		Gain of MoRF binding (P = 0.0678)
MVP		0.86
MPC		0.62
ClinPred		0.54	D
GERP RS		3.5
Varity_R		0.93
gMVP		0.70
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs121908728; hg19: chr20-43254234;