20-44621032-CCTCTT-CCTCTTCTCTT

Variant names:

• chr20-44621032-C-CCTCTT
• rs771266745
• NM_000022.4:c.956_960dupAAGAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000022.4(ADA):​c.956_960dupAAGAG​(p.Glu321LysfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADA NM_000022.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.565
• Publications: 7 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.956_960dupAAGAG	p.Glu321LysfsTer7	frameshift_variant	Exon 10 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.884_888dupAAGAG	p.Glu297LysfsTer7	frameshift_variant	Exon 9 of 11		NP_001308980.1
ADA	NM_001322050.2	c.551_555dupAAGAG	p.Glu186LysfsTer7	frameshift_variant	Exon 9 of 11		NP_001308979.1
ADA	NR_136160.2	n.983_987dupAAGAG		non_coding_transcript_exon_variant	Exon 9 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.956_960dupAAGAG	p.Glu321LysfsTer7	frameshift_variant	Exon 10 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.566_570dupAAGAG	p.Glu191LysfsTer7	frameshift_variant	Exon 7 of 9			ENSP00000512318.1
ADA	ENST00000695991.1	c.494_498dupAAGAG	p.Glu167LysfsTer7	frameshift_variant	Exon 6 of 8			ENSP00000512314.1
ADA	ENST00000695956.1	c.110_114dupAAGAG	p.Glu39fs	frameshift_variant	Exon 1 of 3			ENSP00000512285.1
ADA	ENST00000696038.1	n.*713_*717dupAAGAG		non_coding_transcript_exon_variant	Exon 8 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*713_*717dupAAGAG		3_prime_UTR_variant	Exon 8 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56

Splicing

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

Other links and lift over

dbSNP: rs771266745; hg19: chr20-43249673;