20-44619850-GCTCGTTGGTTC-G

Position:

• chr20-44619850-GCTCGTTGGTTC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000695956.1(ADA):​c.233-1_242delGAACCAACGAG​(p.Glu78fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as no classification for the single variant (no stars). Synonymous variant affecting the same amino acid position (i.e. E78E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADA ENST00000695956.1 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.854

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]

ADA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.379 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.1079-14_1079-4delGAACCAACGAG		splice_region_variant, intron_variant		ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.1007-14_1007-4delGAACCAACGAG		splice_region_variant, intron_variant			NP_001308980.1
ADA	NM_001322050.2	c.674-14_674-4delGAACCAACGAG		splice_region_variant, intron_variant			NP_001308979.1
ADA	NR_136160.2	n.1106-14_1106-4delGAACCAACGAG		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.1079-14_1079-4delGAACCAACGAG		splice_region_variant, intron_variant		1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.689-14_689-4delGAACCAACGAG		splice_region_variant, intron_variant				ENSP00000512318.1
ADA	ENST00000695991.1	c.617-14_617-4delGAACCAACGAG		splice_region_variant, intron_variant				ENSP00000512314.1
ADA	ENST00000695956.1	c.233-1_242delGAACCAACGAG	p.Glu78fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	3/3			ENSP00000512285.1
ADA	ENST00000696038.1	n.*1273_*1283delGAACCAACGAG		non_coding_transcript_exon_variant	9/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*1273_*1283delGAACCAACGAG		3_prime_UTR_variant	9/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr20-43248491;