chr20-44623002-C-T

Variant names:

• chr20-44623002-C-T
• rs763478578
• ENST00000696038.1:n.*429G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000696038.1(ADA):​n.*429G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADA ENST00000696038.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.678+5G>A		splice_region_variant, intron_variant	Intron 7 of 11	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.607-72G>A		intron_variant	Intron 6 of 10		NP_001308980.1
ADA	NM_001322050.2	c.273+5G>A		splice_region_variant, intron_variant	Intron 6 of 10		NP_001308979.1
ADA	NR_136160.2	n.770+5G>A		splice_region_variant, intron_variant	Intron 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000696038.1	n.*429G>A		non_coding_transcript_exon_variant	Exon 7 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*429G>A		3_prime_UTR_variant	Exon 7 of 9			ENSP00000512344.1
ADA	ENST00000372874.9	c.678+5G>A		splice_region_variant, intron_variant	Intron 7 of 11	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.288+5G>A		splice_region_variant, intron_variant	Intron 4 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-72G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251482 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.97
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 5

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

Other links and lift over

dbSNP: rs763478578; hg19: chr20-43251643;