rs121908724

chr20-44636264-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000022.4(ADA):c.58G>A(p.Gly20Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,609,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1 O:1
• Conservation: PhyloP100: 6.08

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]

ACMG classification

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 0 benign, 5 uncertain in NM_000022.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 20-44636264-C-T is Pathogenic according to our data. Variant chr20-44636264-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44636264-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA	NM_000022.4	c.58G>A	p.Gly20Arg	missense_variant	2/12	ENST00000372874.9
ADA	NM_001322051.2	c.58G>A	p.Gly20Arg	missense_variant	2/11
ADA	NM_001322050.2	c.-232G>A		5_prime_UTR_variant	2/11
ADA	NR_136160.2	n.150G>A		non_coding_transcript_exon_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA	ENST00000372874.9	c.58G>A	p.Gly20Arg	missense_variant	2/12	1	NM_000022.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1457312 Hom.: 0 Cov.: 30 AF XY: 0.00000690 AC XY: 5 AN XY: 724514

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:4 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 10, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 20 of the ADA protein (p.Gly20Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8299233, 32445296). ClinVar contains an entry for this variant (Variation ID: 68267). 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 expected to disrupt ADA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 8299233). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 24, 2023	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	Mar 16, 2018	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8299233, 32445296) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.99		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.99
MPC		0.69
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.96

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

Other links and lift over

dbSNP: rs121908724; hg19: chr20-43264905;