20-44624192-C-T

Variant names:

• chr20-44624192-C-T
• rs201045221
• NM_000022.4:c.606+10G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000022.4(ADA):​c.606+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,607,058 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: ADA NM_000022.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.688

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-44624192-C-T is Benign according to our data. Variant chr20-44624192-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434080.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr20-44624192-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000604 (92/152322) while in subpopulation AMR AF= 0.00144 (22/15306). AF 95% confidence interval is 0.000972. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.606+10G>A		intron_variant	Intron 6 of 11	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.606+10G>A		intron_variant	Intron 6 of 10		NP_001308980.1
ADA	NM_001322050.2	c.201+10G>A		intron_variant	Intron 5 of 10		NP_001308979.1
ADA	NR_136160.2	n.698+10G>A		intron_variant	Intron 6 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.606+10G>A		intron_variant	Intron 6 of 11	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-1114G>A		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-1262G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.*352+10G>A		intron_variant	Intron 6 of 8			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000627 AC: 149 AN: 237454 Hom.: 0 AF XY: 0.000778 AC XY: 100 AN XY: 128508

Gnomad AFR exome AF: 0.0000675

Gnomad AMR exome AF: 0.000481

Gnomad ASJ exome AF: 0.00391

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000885

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000603

Gnomad OTH exome AF: 0.000684

GnomAD4 exome AF: 0.000718 AC: 1044 AN: 1454736 Hom.: 2 Cov.: 30 AF XY: 0.000737 AC XY: 533 AN XY: 723146

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000436

Gnomad4 ASJ exome AF: 0.00332

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000727

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000752

Gnomad4 OTH exome AF: 0.000632

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000628 Hom.: 0

Bravo AF: 0.000514

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Benign:4

Oct 25, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 11, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Jan 10, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ADA-related disorder Benign:1

Jul 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADA: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.60
DANN	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201045221; hg19: chr20-43252833;