rs61737144

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000022.4(ADA):c.390G>A(p.Val130Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,570,220 control chromosomes in the GnomAD database, including 1,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 141 hom., cov: 32)

Exomes 𝑓: 0.034 ( 871 hom. )

Consequence

ADA
NM_000022.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.08

Publications

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

ADA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 20-44625657-C-T is Benign according to our data. Variant chr20-44625657-C-T is described in ClinVar as Benign. ClinVar VariationId is 35653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4 link	c.390G>A	p.Val130Val	synonymous_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 link	c.390G>A	p.Val130Val	synonymous_variant	Exon 5 of 11		NP_001308980.1	F5GWI4
ADA	NR_136160.2 link	n.482G>A		non_coding_transcript_exon_variant	Exon 5 of 11
ADA	NM_001322050.2 link	c.73+799G>A		intron_variant	Intron 4 of 10		NP_001308979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 link	c.390G>A	p.Val130Val	synonymous_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000696038.1 link	n.*136G>A		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000696038.1 link	n.*136G>A		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000695995.1 link	c.217-2579G>A		intron_variant	Intron 3 of 8			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 link	c.217-2727G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1	A0A0S2Z3B9

Frequencies

GnomAD3 genomes

AF:

0.0398

AC:

6056

AN:

152178

Hom.:

141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0581

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0310

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.0449

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0350

Gnomad OTH

AF:

0.0383

GnomAD2 exomes

AF:

0.0301

AC:

5382

AN:

179032

AF XY:

0.0296

show subpopulations

Gnomad AFR exome

AF:

0.0618

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.0452

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.0412

Gnomad NFE exome

AF:

0.0354

Gnomad OTH exome

AF:

0.0335

GnomAD4 exome

AF:

0.0337

AC:

47801

AN:

1417924

Hom.:

871

Cov.:

AF XY:

0.0331

AC XY:

23236

AN XY:

701200

show subpopulations

African (AFR)

AF:

0.0593

AC:

1932

AN:

32600

American (AMR)

AF:

0.0175

AC:

677

AN:

38580

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

1049

AN:

25284

East Asian (EAS)

AF:

0.000133

AC:

AN:

37598

South Asian (SAS)

AF:

0.0171

AC:

1381

AN:

80666

European-Finnish (FIN)

AF:

0.0429

AC:

2157

AN:

50228

Middle Eastern (MID)

AF:

0.0316

AC:

172

AN:

5444

European-Non Finnish (NFE)

AF:

0.0352

AC:

38317

AN:

1088822

Other (OTH)

AF:

0.0360

AC:

2111

AN:

58702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

2486

4973

7459

9946

12432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1496

2992

4488

5984

7480

<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:

0.0398

AC:

6063

AN:

152296

Hom.:

141

Cov.:

AF XY:

0.0390

AC XY:

2907

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0582

AC:

2417

AN:

41558

American (AMR)

AF:

0.0309

AC:

473

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

150

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0137

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0449

AC:

477

AN:

10626

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0350

AC:

2382

AN:

68014

Other (OTH)

AF:

0.0379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

300

601

901

1202

1502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0373

Hom.:

Bravo

AF:

0.0394

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jan 18, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, silent variant not near splice site, 2 labs submitted as benign to clinvar -

not provided

Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Severe combined immunodeficiency disease

Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.8

(source)

DANN

Benign

0.76

PhyloP100

1.1

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over