rs761242509

Variant names:

• chr20-44625568-C-G
• NM_000022.4:c.478+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr20-44625568-C-G
• chr20-44625568-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000022.4(ADA):​c.478+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADA NM_000022.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-44625568-C-G is Pathogenic according to our data. Variant chr20-44625568-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2680728.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.478+1G>C		splice_donor_variant, intron_variant	Intron 5 of 11	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.478+1G>C		splice_donor_variant, intron_variant	Intron 5 of 10		NP_001308980.1
ADA	NM_001322050.2	c.73+888G>C		intron_variant	Intron 4 of 10		NP_001308979.1
ADA	NR_136160.2	n.570+1G>C		splice_donor_variant, intron_variant	Intron 5 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.478+1G>C		splice_donor_variant, intron_variant	Intron 5 of 11	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-2490G>C		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2638G>C		intron_variant	Intron 3 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.*224+1G>C		splice_donor_variant, intron_variant	Intron 5 of 8			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 11, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43254209;