20-44625628-C-T

Variant names:

• chr20-44625628-C-T
• rs121908732
• NM_000022.4:c.419G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000022.4(ADA):​c.419G>A​(p.Gly140Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,431,788 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G140R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.54
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.419G>A	p.Gly140Glu	missense_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.419G>A	p.Gly140Glu	missense_variant	Exon 5 of 11		NP_001308980.1
ADA	NR_136160.2	n.511G>A		non_coding_transcript_exon_variant	Exon 5 of 11
ADA	NM_001322050.2	c.73+828G>A		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.419G>A	p.Gly140Glu	missense_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000696038.1	n.*165G>A		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*165G>A		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1
ADA	ENST00000695995.1	c.217-2550G>A		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2698G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000498 AC: 1 AN: 200860 AF XY: 0.00000927

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: 0.0000563

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1431788 Hom.: 0 Cov.: 31 AF XY: 0.00000564 AC XY: 4 AN XY: 709334

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

American (AMR) AF: 0.00 AC: 0 AN: 40758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.00 AC: 0 AN: 38410

South Asian (SAS) AF: 0.00 AC: 0 AN: 81936

European-Finnish (FIN) AF: 0.0000979 AC: 5 AN: 51090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096686

Other (OTH) AF: 0.0000169 AC: 1 AN: 59226

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.
PhyloP100		7.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.93		Loss of catalytic residue at Q138 (P = 0.0867);Loss of catalytic residue at Q138 (P = 0.0867);
MVP		0.96
MPC		0.72
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.96
Mutation Taster		=2/98	disease causing

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: rs121908732; hg19: chr20-43254269; COSMIC: COSV106535596; COSMIC: COSV106535596;