20-44625622-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1).This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA266009/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 2 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:11O:1

Conservation

PhyloP100: 1.47

Publications

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

ADA links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADA	NM_000022.4	MANE Select	c.425G>A	p.Arg142Gln	missense	Exon 5 of 12	NP_000013.2
ADA	NM_001322051.2		c.425G>A	p.Arg142Gln	missense	Exon 5 of 11	NP_001308980.1	F5GWI4
ADA	NM_001322050.2		c.73+834G>A		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.425G>A	p.Arg142Gln	missense	Exon 5 of 12	ENSP00000361965.4	P00813
ADA	ENST00000537820.2	TSL:1	c.425G>A	p.Arg142Gln	missense	Exon 5 of 11	ENSP00000441818.1	F5GWI4
ADA	ENST00000695995.1		c.217-2544G>A		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00101

AC:

204

AN:

202328

AF XY:

0.000681

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000643

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000690

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000431

AC:

617

AN:

1432964

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

266

AN XY:

710034

show subpopulations

African (AFR)

AF:

0.0132

AC:

437

AN:

33006

American (AMR)

AF:

0.000781

AC:

AN:

40982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25444

East Asian (EAS)

AF:

0.0000520

AC:

AN:

38466

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51150

Middle Eastern (MID)

AF:

0.000586

AC:

AN:

5122

European-Non Finnish (NFE)

AF:

0.0000765

AC:

AN:

1097470

Other (OTH)

AF:

0.000979

AC:

AN:

59256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00370

AC:

564

AN:

152306

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0129

AC:

538

AN:

41568

American (AMR)

AF:

0.00111

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0190

Hom.:

2349

Bravo

AF:

0.00440

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00119

AC:

143

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

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 (8)

not provided (4)

ADA-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0086

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.5

PhyloP100

1.5

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

REVEL

Benign

0.25

Sift

Benign

0.47

Sift4G

Benign

0.35

Polyphen

0.024

Vest4

0.39

MVP

0.84

MPC

0.17

ClinPred

0.015

GERP RS

-0.31

Varity_R

0.087

gMVP

0.43

Mutation Taster

=88/12

polymorphism

(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

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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