NM_000022.4:c.425G>C

Variant names:

• chr20-44625622-C-G
• rs61732239
• NM_000022.4:c.425G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000022.4(ADA):​c.425G>C​(p.Arg142Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.425G>C	p.Arg142Pro	missense_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.425G>C	p.Arg142Pro	missense_variant	Exon 5 of 11		NP_001308980.1
ADA	NR_136160.2	n.517G>C		non_coding_transcript_exon_variant	Exon 5 of 11
ADA	NM_001322050.2	c.73+834G>C		intron_variant	Intron 4 of 10		NP_001308979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.425G>C	p.Arg142Pro	missense_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000696038.1	n.*171G>C		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*171G>C		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1
ADA	ENST00000695995.1	c.217-2544G>C		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2692G>C		intron_variant	Intron 3 of 7			ENSP00000512314.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432964 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710034

African (AFR) AF: 0.00 AC: 0 AN: 33006

American (AMR) AF: 0.00 AC: 0 AN: 40982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25444

East Asian (EAS) AF: 0.00 AC: 0 AN: 38466

South Asian (SAS) AF: 0.00 AC: 0 AN: 82068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097470

Other (OTH) AF: 0.00 AC: 0 AN: 59256

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2349

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Benign	0.18
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.5	H;.
PhyloP100		1.5
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.063	T;T
Polyphen		0.89	P;.
Vest4		0.61
MutPred		0.69		Loss of solvent accessibility (P = 0.0364);Loss of solvent accessibility (P = 0.0364);
MVP		0.94
MPC		0.63
ClinPred		0.98	D
GERP RS		-0.31
Varity_R		0.93
gMVP		0.86
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs61732239; hg19: chr20-43254263;