20-44620297-A-T

Variant names:

• chr20-44620297-A-T
• rs1555843178
• NM_000022.4:c.1078+2T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_Moderate PM2_Supporting PVS1_Moderate PM3

This summary comes from the ClinGen Evidence Repository: The c.1078+2T>A (NM_000022.4) variant in ADA occurs within the canonical splice donor site (+2) of intron 11. It is predicted to cause skipping of biologically relevant exon by SpliceAI (Δ score = Donor Loss = 0.97); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; PVS1_Moderate.This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient present: Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), reaching 3 points, PP4_Moderate.This variant has been detected in 02 individuals with ADA SCID. One of them is compound heterozygous with c.955-958delGAAG, p.E320RfsX6, a frameshift termination, which is at least LP according to SCID VCEP. Phase is unknown, so 0.5 pt; The second one is compound heterozygous, for c.482G > A, p.W161X (Also at least LP according to SCID VCEP). Phase is not shown. 0.5pts. Total is 1 pt, PM3_Moderate (PMIDs: 32307643 and 26255240).In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PVS1_Strong, PP4_Moderate, and PM3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409118270/MONDO:0007064/114

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADA NM_000022.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 2.50

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]

PKIG (HGNC:9019): (cAMP-dependent protein kinase inhibitor gamma) This gene encodes a member of the protein kinase inhibitor family. Studies of a similar protein in mice suggest that this protein acts as a potent competitive cAMP-dependent protein kinase inhibitor, and is a predominant form of inhibitor in various tissues. The encoded protein may be involved in osteogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.1078+2T>A		splice_donor_variant, intron_variant	Intron 11 of 11	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.1006+2T>A		splice_donor_variant, intron_variant	Intron 10 of 10		NP_001308980.1
ADA	NM_001322050.2	c.673+2T>A		splice_donor_variant, intron_variant	Intron 10 of 10		NP_001308979.1
ADA	NR_136160.2	n.1105+2T>A		splice_donor_variant, intron_variant	Intron 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.1078+2T>A		splice_donor_variant, intron_variant	Intron 11 of 11	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.688+2T>A		splice_donor_variant, intron_variant	Intron 8 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.616+2T>A		splice_donor_variant, intron_variant	Intron 7 of 7			ENSP00000512314.1
ADA	ENST00000695956.1	c.232+2T>A		splice_donor_variant, intron_variant	Intron 2 of 2			ENSP00000512285.1
ADA	ENST00000696038.1	n.*837T>A		non_coding_transcript_exon_variant	Exon 9 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*837T>A		3_prime_UTR_variant	Exon 9 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727030

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:2

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1078+2T>A (NM_000022.4) variant in ADA occurs within the canonical splice donor site (+2) of intron 11. It is predicted to cause skipping of biologically relevant exon by SpliceAI (Δ score = Donor Loss = 0.97); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; PVS1_Moderate. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient present: Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), reaching 3 points, PP4_Moderate. This variant has been detected in 02 individuals with ADA SCID. One of them is compound heterozygous with c.955-958delGAAG, p.E320RfsX6, a frameshift termination, which is at least LP according to SCID VCEP. Phase is unknown, so 0.5 pt; The second one is compound heterozygous, for c.482G > A, p.W161X (Also at least LP according to SCID VCEP). Phase is not shown. 0.5pts. Total is 1 pt, PM3_Moderate (PMIDs: 32307643 and 26255240). In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PVS1_Strong, PP4_Moderate, and PM3_Moderate. -

May 14, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.97
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555843178; hg19: chr20-43248938;