chr20-44625581-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000022.4(ADA):c.466C>A(p.Arg156Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.57

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: 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000022.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-44625580-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 20-44625581-G-T is Pathogenic according to our data. Variant chr20-44625581-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3251901.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4 link	c.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 link	c.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 11		NP_001308980.1	F5GWI4
ADA	NR_136160.2 link	n.558C>A		non_coding_transcript_exon_variant	Exon 5 of 11
ADA	NM_001322050.2 link	c.73+875C>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.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000696038.1 link	n.*212C>A		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000696038.1 link	n.*212C>A		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000695995.1 link	c.217-2503C>A		intron_variant	Intron 3 of 8			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 link	c.217-2651C>A		intron_variant	Intron 3 of 7			ENSP00000512314.1	A0A0S2Z3B9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1429860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708270

African (AFR)

AF:

0.00

AC:

AN:

32924

American (AMR)

AF:

0.00

AC:

AN:

40390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25424

East Asian (EAS)

AF:

0.00

AC:

AN:

38324

South Asian (SAS)

AF:

0.00

AC:

AN:

81832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4568

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096334

Other (OTH)

AF:

0.00

AC:

AN:

59086

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe combined immunodeficiency disease

Pathogenic:1

Apr 17, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ADA c.466C>A (p.Arg156Ser) results in a non-conservative amino acid change located in the adenosine deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 202092 control chromosomes. To our knowledge, no occurrence of c.466C>A in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. Different variants affecting the same codon has been classified as pathogenic by our lab (c.466C>T, p.Arg156Cys; c.467G>A, p.Arg156His), supporting the critical relevance of codon 156 to ADA protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;.

PhyloP100

9.6

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.92

Loss of MoRF binding (P = 0.0148);Loss of MoRF binding (P = 0.0148);

MVP

0.96

MPC

0.67

ClinPred

1.0

GERP RS

4.7

Varity_R

0.97

gMVP

0.94

Mutation Taster

=19/81

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over