chr20-44620212-T-C

Position:

• chr20-44620212-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000022.4(ADA):​c.1078+87A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0558 in 1,187,104 control chromosomes in the GnomAD database, including 2,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (557 hom., cov: 33)
  • Exomes 𝑓: 0.053 (1824 hom.)
• Consequence: ADA NM_000022.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.187

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-44620212-T-C is Benign according to our data. Variant chr20-44620212-T-C is described in ClinVar as [Benign]. Clinvar id is 1173013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.1078+87A>G		intron_variant		ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.1006+87A>G		intron_variant			NP_001308980.1
ADA	NM_001322050.2	c.673+87A>G		intron_variant			NP_001308979.1
ADA	NR_136160.2	n.1105+87A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.1078+87A>G		intron_variant		1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.688+87A>G		intron_variant				ENSP00000512318.1
ADA	ENST00000695991.1	c.616+87A>G		intron_variant				ENSP00000512314.1
ADA	ENST00000695956.1	c.232+87A>G		intron_variant				ENSP00000512285.1
ADA	ENST00000696038.1	n.*922A>G		non_coding_transcript_exon_variant	9/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*922A>G		3_prime_UTR_variant	9/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11167 AN: 152168 Hom.: 556 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0563

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.0721

GnomAD4 exome AF: 0.0532 AC: 55041 AN: 1034818 Hom.: 1824 AF XY: 0.0536 AC XY: 28635 AN XY: 533882

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.0710

Gnomad4 ASJ exome AF: 0.0773

Gnomad4 EAS exome AF: 0.000583

Gnomad4 SAS exome AF: 0.0642

Gnomad4 FIN exome AF: 0.0461

Gnomad4 NFE exome AF: 0.0496

Gnomad4 OTH exome AF: 0.0618

GnomAD4 genome AF: 0.0734 AC: 11183 AN: 152286 Hom.: 557 Cov.: 33 AF XY: 0.0723 AC XY: 5388 AN XY: 74476

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0563

Gnomad4 ASJ AF: 0.0784

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0634

Gnomad4 FIN AF: 0.0419

Gnomad4 NFE AF: 0.0500

Gnomad4 OTH AF: 0.0718

Alfa AF: 0.0650 Hom.: 90

Bravo AF: 0.0782

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs45567037; hg19: chr20-43248853;