20-44651586-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000022.4(ADA):c.22G>T(p.Asp8Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D8N) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.538

Publications

81 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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000022.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3410142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4 link	c.22G>T	p.Asp8Tyr	missense_variant	Exon 1 of 12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 link	c.22G>T	p.Asp8Tyr	missense_variant	Exon 1 of 11		NP_001308980.1	F5GWI4
ADA	NR_136160.2 link	n.114G>T		non_coding_transcript_exon_variant	Exon 1 of 11
ADA	NM_001322050.2 link	c.-268G>T		5_prime_UTR_variant	Exon 1 of 11		NP_001308979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 link	c.22G>T	p.Asp8Tyr	missense_variant	Exon 1 of 12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000695995.1 link	c.22G>T	p.Asp8Tyr	missense_variant	Exon 1 of 9			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 link	c.22G>T	p.Asp8Tyr	missense_variant	Exon 1 of 8			ENSP00000512314.1	A0A0S2Z3B9
ADA	ENST00000696038.1 link	n.22G>T		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512344.1	A0A8Q3SJ57

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000713

AC:

AN:

140254

AF XY:

0.00

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:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1388788

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31096

American (AMR)

AF:

0.00

AC:

AN:

37182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25056

East Asian (EAS)

AF:

0.00

AC:

AN:

35892

South Asian (SAS)

AF:

0.00

AC:

AN:

79900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4548

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1083012

Other (OTH)

AF:

0.00

AC:

AN:

57842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.79

D;T

Eigen

Benign

-0.057

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.5

L;.

PhyloP100

-0.54

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.57

Sift

Uncertain

0.010

D;D

Sift4G

Benign

0.061

T;T

Polyphen

0.92

P;.

Vest4

0.41

MutPred

0.45

Loss of disorder (P = 0.0194);Loss of disorder (P = 0.0194);

MVP

0.99

MPC

0.56

ClinPred

0.62

GERP RS

-1.4

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.63

gMVP

0.71

Mutation Taster

=89/11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over