rs116962828

Variant names:

• chr20-44622599-A-G
• rs116962828
• NM_000022.4:c.834T>C
• ADA p.His278His

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000022.4(ADA):​c.834T>C​(p.His278His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,234 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene ADA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (38 hom.)
• Consequence: ADA NM_000022.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.401
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-44622599-A-G is Benign according to our data. Variant chr20-44622599-A-G is described in ClinVar as Benign. ClinVar VariationId is 338505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.401 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00661 (1007/152346) while in subpopulation EAS AF = 0.0251 (130/5174). AF 95% confidence interval is 0.0216. There are 12 homozygotes in GnomAd4. There are 493 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.834T>C	p.His278His	synonymous	Exon 9 of 12	NP_000013.2
	ADA	NM_001322051.2		c.762T>C	p.His254His	synonymous	Exon 8 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.429T>C	p.His143His	synonymous	Exon 8 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.834T>C	p.His278His	synonymous	Exon 9 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.762T>C	p.His254His	synonymous	Exon 8 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.444T>C	p.His148His	synonymous	Exon 6 of 9	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152230 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00408 AC: 1026 AN: 251368 AF XY: 0.00380

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00186 AC: 2718 AN: 1461888 Hom.: 38 Cov.: 32 AF XY: 0.00190 AC XY: 1383 AN XY: 727246

African (AFR) AF: 0.0184 AC: 617 AN: 33480

American (AMR) AF: 0.00165 AC: 74 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0313 AC: 1243 AN: 39698

South Asian (SAS) AF: 0.00446 AC: 385 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000160 AC: 178 AN: 1112010

Other (OTH) AF: 0.00329 AC: 199 AN: 60396

GnomAD4 genome AF: 0.00661 AC: 1007 AN: 152346 Hom.: 12 Cov.: 33 AF XY: 0.00662 AC XY: 493 AN XY: 74498

African (AFR) AF: 0.0184 AC: 765 AN: 41574

American (AMR) AF: 0.00313 AC: 48 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0251 AC: 130 AN: 5174

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00331 Hom.: 4

Bravo AF: 0.00762

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (3)
-	-	1	ADA-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.32
DANN	Benign	0.76
PhyloP100		-0.40
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs116962828; hg19: chr20-43251240;