20-44625662-C-A

Position:

• chr20-44625662-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000022.4(ADA):​c.385G>T​(p.Val129Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,356 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V129M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.54

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44625662-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 20-44625662-C-A is Pathogenic according to our data. Variant chr20-44625662-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1491839.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.385G>T	p.Val129Leu	missense_variant	5/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.385G>T	p.Val129Leu	missense_variant	5/11		NP_001308980.1
ADA	NM_001322050.2	c.73+794G>T		intron_variant			NP_001308979.1
ADA	NR_136160.2	n.477G>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.385G>T	p.Val129Leu	missense_variant	5/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1415356 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699674

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 03, 2023

This variant has not been reported in the literature in individuals affected with ADA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 129 of the ADA protein (p.Val129Leu). ClinVar contains an entry for this variant (Variation ID: 1491839). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val129 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10200056, 26255240, 26376800). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.90		Gain of phosphorylation at T125 (P = 0.226);Gain of phosphorylation at T125 (P = 0.226);
MVP		0.90
MPC		0.61
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs121908731; hg19: chr20-43254303;