20-44625662-C-T

Variant names:

• chr20-44625662-C-T
• rs121908731
• NM_000022.4:c.385G>A

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.385G>A​(p.Val129Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000424 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 20-44625662-C-T is Pathogenic according to our data. Variant chr20-44625662-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44625662-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.385G>A	p.Val129Met	missense_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.385G>A	p.Val129Met	missense_variant	Exon 5 of 11		NP_001308980.1
ADA	NM_001322050.2	c.73+794G>A		intron_variant	Intron 4 of 10		NP_001308979.1
ADA	NR_136160.2	n.477G>A		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.385G>A	p.Val129Met	missense_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-2584G>A		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2732G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.*131G>A		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*131G>A		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000424 AC: 6 AN: 1415356 Hom.: 0 Cov.: 31 AF XY: 0.00000572 AC XY: 4 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: 0.00000552

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 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 Other:1

Sep 16, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 129 of the ADA protein (p.Val129Met). 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: 10200056, 26255240, 26376800). ClinVar contains an entry for this variant (Variation ID: 68260). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 12, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.94		Gain of disorder (P = 0.1262);Gain of disorder (P = 0.1262);
MVP		0.91
MPC		0.63
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;