20-44625568-C-T

Variant names:

• chr20-44625568-C-T
• rs761242509
• NM_000022.4:c.478+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000022.4(ADA):​c.478+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,575,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002060164: Functional assessments of this variant are available in the literature (PMID:7599635)." and additional evidence is available in ClinVar. The gene ADA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: ADA NM_000022.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.54
• 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]

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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002060164: Functional assessments of this variant are available in the literature (PMID: 7599635).; SCV002557227: "Moderate functional evidence supporting abnormal protein function as shown that ADA activity was reduced compared to wild-type and carriers (PMID: 8673127)."; SCV000321375: This pathogenic variant destroys the canonical splice donor site in intron 5, and has been shown to cause abnormal gene splicing (Santisteban et al., 1995).; SCV006325041: Experimental studies evaluating impact of this variant on mRNA splicing showed deletion of exon 5 and premature termination (PMID: 7599635, PMID: 8673127).; SCV001339001: The variant allele was found at a frequency of 2.1e-05 in 193792 control chromosomes (gnomAD). c.478+1G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome (Santisteban_1995, Hirschhorn_1996). These data indicate that the variant may be associated with disease. no
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-44625568-C-T is Pathogenic according to our data. Variant chr20-44625568-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 265025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.478+1G>A		splice_donor intron	N/A	NP_000013.2
	ADA	NM_001322051.2		c.478+1G>A		splice_donor intron	N/A	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.73+888G>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.478+1G>A		splice_donor intron	N/A	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.478+1G>A		splice_donor intron	N/A	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.217-2490G>A		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152198 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000206 AC: 4 AN: 193792 AF XY: 0.0000289

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: 0.0000486

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000611 AC: 87 AN: 1423636 Hom.: 0 Cov.: 31 AF XY: 0.0000568 AC XY: 40 AN XY: 704604

African (AFR) AF: 0.00 AC: 0 AN: 32806

American (AMR) AF: 0.00 AC: 0 AN: 39432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 38006

South Asian (SAS) AF: 0.00 AC: 0 AN: 81230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4450

European-Non Finnish (NFE) AF: 0.0000741 AC: 81 AN: 1092906

Other (OTH) AF: 0.0000849 AC: 5 AN: 58860

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (8)
2	-	-	not provided (2)
1	-	-	Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.5
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761242509; hg19: chr20-43254209;