NM_000022.4:c.396dupA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4PVS1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.396dup (p.Val133Serfs*38) (NM_000022.4) variant in ADA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pt) + T-B-NK- lymphocyte subset profile (0.5pt) = 1 point TOTAL, which is highly specific for SCID (PP4_Met, PMID:21664875). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA658824668/MONDO:0007064/114

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ADA
NM_000022.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: -0.841

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

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

PM2

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

PP4

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.396dupA	p.Val133SerfsTer38	frameshift	Exon 5 of 12	NP_000013.2
ADA	NM_001322051.2		c.396dupA	p.Val133SerfsTer38	frameshift	Exon 5 of 11	NP_001308980.1	F5GWI4
ADA	NM_001322050.2		c.73+805dupA		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.396dupA	p.Val133SerfsTer38	frameshift	Exon 5 of 12	ENSP00000361965.4	P00813
ADA	ENST00000537820.2	TSL:1	c.396dupA	p.Val133SerfsTer38	frameshift	Exon 5 of 11	ENSP00000441818.1	F5GWI4
ADA	ENST00000695995.1		c.217-2573dupA		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1422060

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703610

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32752

American (AMR)

AF:

0.00

AC:

AN:

39176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25310

East Asian (EAS)

AF:

0.00

AC:

AN:

37886

South Asian (SAS)

AF:

0.00

AC:

AN:

81044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091128

Other (OTH)

AF:

0.00

AC:

AN:

58840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

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 (5)

Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.84

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: 34

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over