rs1555843178

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-44620297-A-G
• chr20-44620297-A-T
• chr20-44620297-A-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 NM_000022.4 splice_donor, intron
• 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: NM_000022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	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	F5GWI4
	ADA	NM_001322050.2		c.673+2T>C		splice_donor intron	N/A	NP_001308979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.1078+2T>C		splice_donor intron	N/A	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.1006+2T>C		splice_donor intron	N/A	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.688+2T>C		splice_donor intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (2)

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;