20-44621103-G-T

Position:

chr20-44621103-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000022.4(ADA):c.890C>A(p.Pro297Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P297L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2O:1

Conservation

PhyloP100: 6.50

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 links:

PKIG (HGNC:9019): (cAMP-dependent protein kinase inhibitor gamma) This gene encodes a member of the protein kinase inhibitor family. Studies of a similar protein in mice suggest that this protein acts as a potent competitive cAMP-dependent protein kinase inhibitor, and is a predominant form of inhibitor in various tissues. The encoded protein may be involved in osteogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PKIG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 4 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-44621103-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1505857.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 20-44621103-G-T is Pathogenic according to our data. Variant chr20-44621103-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1961.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=2}. Variant chr20-44621103-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADA	NM_000022.4 linkuse as main transcript	c.890C>A	p.Pro297Gln	missense_variant	10/12	ENST00000372874.9
ADA	NM_001322051.2 linkuse as main transcript	c.818C>A	p.Pro273Gln	missense_variant	9/11
ADA	NM_001322050.2 linkuse as main transcript	c.485C>A	p.Pro162Gln	missense_variant	9/11
ADA	NR_136160.2 linkuse as main transcript	n.917C>A		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.890C>A	p.Pro297Gln	missense_variant	10/12	1	NM_000022.4	P4

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251492

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000125

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:2Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 297 of the ADA protein (p.Pro297Gln). This variant is present in population databases (rs121908718, gnomAD 0.02%). This missense change has been observed in individual(s) with partial adenosine deaminase (ADA) deficiency (PMID: 2166947, 2783588). ClinVar contains an entry for this variant (Variation ID: 1961). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADA protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ADA function (PMID: 2166947). This variant disrupts the p.Pro297 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as transfection of the mutant cDNA into heterologous cells resulted in expression of a heat-labile ADA of normal electrophoretic mobility, properties exhibited by the ADA in the patients' cells (Hirschhorn et al., 1989); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9225964, 2783588, 21898656, 24772956, 20493397, 2166947, 31589614, 34975878, 23645737) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 01, 2021	- -

Partial adenosine deaminase deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1989

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 12, 2022

Variant summary: ADA c.890C>A (p.Pro297Gln) 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 allele was found at a frequency of 2.8e-05 in 251492 control chromosomes (gnomAD). c.890C>A has been reported in the literature in the homozygous and compound heterozygous states in two partially ADA deficient children, identified through Newborn Screening (Hirschhorn_1989, Hirschhorn_1990). A later report by the same authors (Hirschhorn_1995) stated that up to that date, the children had not presented with immunodeficiency. GeneReviews defines partial ADA deficiency as a benign condition which is compatible with normal immune function (PMID 20301656). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. Experimental evidence evaluating an impact on protein function demonstrated the variant to have normal electrophoretic mobility and abnormal heat stability, with ADA activity measured at 56% in homozygous lymphoid cells (Hirschhorn_1989, Hirschhorn_1990). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.80

MutPred

0.97

Gain of ubiquitination at K301 (P = 0.0843);.;

MVP

0.97

MPC

0.54

ClinPred

0.98

GERP RS

5.0

Varity_R

0.92

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over