20-44620297-A-G

Variant names:

• chr20-44620297-A-G
• rs1555843178
• ENST00000696038.1:n.*837T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PS1_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1078+2T>C (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 = 0.96); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; Variant removes <10% of protein. PVS1_Moderate. This variant is absent from gnomAD v.4 (PM2_Supporting). The intronic change (c.1078+2T>A) is classified as Likely Pathogenic for ADA-SCID by the ClinGen SCID VCEP (PS1_Moderate).To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Moderate, PM2_Supporting, and PS1_Modetate (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA409118267/MONDO:0007064/114

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADA ENST00000696038.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 0.9607
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 2.50
• Publications: 0 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]

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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000696038.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.1078+2T>C		splice_donor intron	N/A	NP_000013.2
	ADA	NM_001322051.2		c.1006+2T>C		splice_donor intron	N/A	NP_001308980.1
	ADA	NM_001322050.2		c.673+2T>C		splice_donor intron	N/A	NP_001308979.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000696038.1		n.*837T>C		non_coding_transcript_exon	Exon 9 of 9	ENSP00000512344.1
	ADA	ENST00000696038.1		n.*837T>C		3_prime_UTR	Exon 9 of 9	ENSP00000512344.1
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.1078+2T>C		splice_donor intron	N/A	ENSP00000361965.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

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:1 Uncertain:1

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1078+2T>C (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 = 0.96); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; Variant removes <10% of protein. PVS1_Moderate. This variant is absent from gnomAD v.4 (PM2_Supporting). The intronic change (c.1078+2T>A) is classified as Likely Pathogenic for ADA-SCID by the ClinGen SCID VCEP (PS1_Moderate). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies. In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Moderate, PM2_Supporting, and PS1_Modetate (VCEP specifications version 1).

Sep 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 2088001). Disruption of this splice site has been observed in individual(s) with severe combined immunodeficiency due to adenosine deaminase deficiency (PMID: 26255240, 32307643). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 11 of the ADA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.5
GERP RS		4.7
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 2

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

Other links and lift over

dbSNP: rs1555843178; hg19: chr20-43248938;