dbSNP rs780014431: ADA:p.Arg142* (chr20-44625623-G-A) – ACMG Classification: Pathogenic (22 pts)

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong

The NM_000022.4(ADA):c.424C>T(p.Arg142*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,585,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001363446: Skipping of exon 5 caused by R142X shifts the reading frame, introducing a new TAA translation stop signal at the 10th codon (Santisteban_1995)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R142R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene ADA is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ADA
NM_000022.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.54

Publications

6 publications found

Variant links:

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

ADA links:

Genome browser will be placed here

ACMG classification

Specifications for ADA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001363446: Skipping of exon 5 caused by R142X shifts the reading frame, introducing a new TAA translation stop signal at the 10th codon (Santisteban_1995).; SCV005360973: Functional studies have reported that this variant leads to a deletion of exon 5 (Santisteban et al. 1995. PubMed ID: 8589684; Valentine. 1998. PubMed ID: 9806422).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-44625623-G-A is Pathogenic according to our data. Variant chr20-44625623-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 552928.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADA	NM_000022.4	MANE Select	c.424C>T	p.Arg142*	stop_gained	Exon 5 of 12	NP_000013.2
ADA	NM_001322051.2		c.424C>T	p.Arg142*	stop_gained	Exon 5 of 11	NP_001308980.1	F5GWI4
ADA	NM_001322050.2		c.73+833C>T		intron	N/A	NP_001308979.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADA	ENST00000372874.9	TSL:1 MANE Select	c.424C>T	p.Arg142*	stop_gained	Exon 5 of 12	ENSP00000361965.4	P00813
ADA	ENST00000537820.2	TSL:1	c.424C>T	p.Arg142*	stop_gained	Exon 5 of 11	ENSP00000441818.1	F5GWI4
ADA	ENST00000695995.1		c.217-2545C>T		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000198

AC:

AN:

202372

AF XY:

0.0000276

show subpopulations

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:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000244

AC:

AN:

1432918

Hom.:

Cov.:

AF XY:

0.0000239

AC XY:

AN XY:

709996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33004

American (AMR)

AF:

0.0000488

AC:

AN:

40972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25444

East Asian (EAS)

AF:

0.0000520

AC:

AN:

38488

South Asian (SAS)

AF:

0.0000731

AC:

AN:

82070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5152

European-Non Finnish (NFE)

AF:

0.0000210

AC:

AN:

1097406

Other (OTH)

AF:

0.0000338

AC:

AN:

59248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000206

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (7)

ADA-related disorder (1)

Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.80

PhyloP100

1.5

Vest4

0.85

GERP RS

1.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over