NM_000022.4:c.22G>C

Variant names:

• chr20-44651586-C-G
• rs73598374
• NM_000022.4:c.22G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000022.4(ADA):​c.22G>C​(p.Asp8His) 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 benign 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. D8N) 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: -0.538
• Publications: 81 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000022.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27966693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.22G>C	p.Asp8His	missense_variant	Exon 1 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.22G>C	p.Asp8His	missense_variant	Exon 1 of 11		NP_001308980.1
ADA	NR_136160.2	n.114G>C		non_coding_transcript_exon_variant	Exon 1 of 11
ADA	NM_001322050.2	c.-268G>C		5_prime_UTR_variant	Exon 1 of 11		NP_001308979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.22G>C	p.Asp8His	missense_variant	Exon 1 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.22G>C	p.Asp8His	missense_variant	Exon 1 of 9			ENSP00000512318.1
ADA	ENST00000695991.1	c.22G>C	p.Asp8His	missense_variant	Exon 1 of 8			ENSP00000512314.1
ADA	ENST00000696038.1	n.22G>C		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 140254 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1388788 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 686854

African (AFR) AF: 0.00 AC: 0 AN: 31096

American (AMR) AF: 0.00 AC: 0 AN: 37182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 35892

South Asian (SAS) AF: 0.00 AC: 0 AN: 79900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083012

Other (OTH) AF: 0.00 AC: 0 AN: 57842

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T;T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.5	L;.
PhyloP100		-0.54
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.094	T;T
Polyphen		0.82	P;.
Vest4		0.27
MutPred		0.26		Loss of ubiquitination at K11 (P = 0.057);Loss of ubiquitination at K11 (P = 0.057);
MVP		0.98
MPC		0.45
ClinPred		0.76	D
GERP RS		-1.4
PromoterAI		-0.10	Neutral
Varity_R		0.40
gMVP		0.61
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73598374; hg19: chr20-43280227;