chr20-44625580-C-T

Position:

• chr20-44625580-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000022.4(ADA):​c.467G>A​(p.Arg156His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000247 in 1,581,258 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. R156C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O: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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44625581-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 20-44625580-C-T is Pathogenic according to our data. Variant chr20-44625580-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44625580-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.467G>A	p.Arg156His	missense_variant	5/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.467G>A	p.Arg156His	missense_variant	5/11		NP_001308980.1
ADA	NM_001322050.2	c.73+876G>A		intron_variant			NP_001308979.1
ADA	NR_136160.2	n.559G>A		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.467G>A	p.Arg156His	missense_variant	5/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-2502G>A		intron_variant				ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2650G>A		intron_variant				ENSP00000512314.1
ADA	ENST00000696038.1	n.*213G>A		non_coding_transcript_exon_variant	5/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*213G>A		3_prime_UTR_variant	5/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 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: 0.0000266 AC: 38 AN: 1429110 Hom.: 0 Cov.: 31 AF XY: 0.0000240 AC XY: 17 AN XY: 707846

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: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000338

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

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:8 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:6 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 23, 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	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Dec 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 156 of the ADA protein (p.Arg156His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ADA-related conditions (PMID: 8227344, 18952502). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1984). 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: 8227344). This variant disrupts the p.Arg156 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1284479, 9758612, 22447032, 26376800). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2017	- -

SCID due to ADA deficiency, delayed onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1996

- -

Severe combined immunodeficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 10, 2019

Variant summary: ADA c.467G>A (p.Arg156His) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain (IPR001365) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-06 in 201072 control chromosomes (gnomAD). c.467G>A has been reported in the literature in multiple individuals affected with ADA deficiency and Combined Immunodeficiency Syndrome. In many cases, this variant was associated with late/delayed onset of immunodeficiency (e.g. Santisteban_1993, Arredondo-Vega_1998). Somatic mosaicism due to an unusual mechanism of 'reversion to normal' of the inherited mutation has been also reported for this variant (e.g. Hirschhorn_1996, Liu_2009); these cases were also associated with a milder disease phenotype. These data indicate that the variant is very likely to be associated with disease. In in vitro assays, the variant resulted in incomplete loss of ADA activity (Santisteban_1993, Jiang_1997, Arredondo-Vega_1998) that might be consistent with the reported delayed-onset disease phenotypes (Arredondo-Vega_1998). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.051	T;D
Sift4G	Benign	0.061	T;T
Polyphen		1.0	D;.
Vest4		0.94
MVP		0.96
MPC		0.70
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.90

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: rs121908722; hg19: chr20-43254221;