rs199422327

Positions:

chr20-44621082-A-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000372874.9(ADA):c.911T>G(p.Leu304Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,104 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L304L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ADA
ENST00000372874.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.11

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 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000372874.9

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 20-44621082-A-C is Pathogenic according to our data. Variant chr20-44621082-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADA	NM_000022.4 linkuse as main transcript	c.911T>G	p.Leu304Arg	missense_variant	10/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2 linkuse as main transcript	c.839T>G	p.Leu280Arg	missense_variant	9/11		NP_001308980.1
ADA	NM_001322050.2 linkuse as main transcript	c.506T>G	p.Leu169Arg	missense_variant	9/11		NP_001308979.1
ADA	NR_136160.2 linkuse as main transcript	n.938T>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.911T>G	p.Leu304Arg	missense_variant	10/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000437

AC:

AN:

251496

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135922

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

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:

0.0000189

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

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:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 304 of the ADA protein (p.Leu304Arg). This variant is present in population databases (rs199422327, gnomAD 0.008%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 46025, 1284479, 17185467). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1006T>G. ClinVar contains an entry for this variant (Variation ID: 1958). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 3007108). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1986	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 10, 2021	NM_000022.2(ADA):c.911T>G(L304R) is a missense variant classified as likely pathogenic in the context of adenosine deaminase deficiency. L304R has been observed in cases with relevant disease (PMID: 17185467, 1346349). Functional assessments of this variant are available in the literature (PMID: 3007108). L304R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000022.2(ADA):c.911T>G(L304R) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

ADA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

The ADA c.911T>G variant is predicted to result in the amino acid substitution p.Leu304Arg. This variant has been reported in an individual with adenosine deaminase deficiency; however, a second pathogenic variant was not identified (Valerio et al. 1986. PubMed ID: 3007108). It has been reported in the compound heterozygous state in individuals with adenosine deaminase deficiency (Table S7, Bell et al. 2011. PubMed ID: 21228398; Rojas-Restrepo et al. 2021. PubMed ID: 34975878). In vitro and in situ functional studies demonstrate this variant alters restriction sites, reduces hydrophobic properties, and produces a protein lacking catalytic activity (Valerio et al. 1986. PubMed ID: 3007108; Rojas-Restrepo et al. 2021. PubMed ID: 34975878). This variant is reported in 0.0097% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 19, 2024

PP3, PM1, PM2, PM3, PS3_supporting, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.97

Loss of stability (P = 0.0053);.;

MVP

0.98

MPC

0.76

ClinPred

1.0

GERP RS

5.5

Varity_R

0.99

gMVP

0.99

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

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