20-44624279-C-T

Position:

• chr20-44624279-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000022.4(ADA):​c.529G>A​(p.Val177Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,738 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 5.61

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 (HGNC:):

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 20-44624279-C-T is Pathogenic according to our data. Variant chr20-44624279-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44624279-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.529G>A	p.Val177Met	missense_variant	6/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.529G>A	p.Val177Met	missense_variant	6/11		NP_001308980.1
ADA	NM_001322050.2	c.124G>A	p.Val42Met	missense_variant	5/11		NP_001308979.1
ADA	NR_136160.2	n.621G>A		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.529G>A	p.Val177Met	missense_variant	6/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-1201G>A		intron_variant				ENSP00000512318.1
ADA	ENST00000695991.1	c.217-1349G>A		intron_variant				ENSP00000512314.1
ADA	ENST00000696038.1	n.*275G>A		non_coding_transcript_exon_variant	6/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*275G>A		3_prime_UTR_variant	6/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251362 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461738 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 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:5 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 177 of the ADA protein (p.Val177Met). This variant is present in population databases (rs121908719, gnomAD 0.006%). This missense change has been observed in individual(s) with ADA-SCID (PMID: 8227344, 26376800). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68265). 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: 9758612). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.93		Gain of catalytic residue at Q173 (P = 0.0843);Gain of catalytic residue at Q173 (P = 0.0843);
MVP		0.98
MPC		0.63
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.87

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: rs121908719; hg19: chr20-43252920;