rs45557242

Positions:

• chr20-44629103-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000022.4(ADA):​c.162G>A​(p.Lys54Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,614,236 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: ADA NM_000022.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.648

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-44629103-C-T is Benign according to our data. Variant chr20-44629103-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 338510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44629103-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.648 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00274 (418/152354) while in subpopulation NFE AF= 0.0036 (245/68032). AF 95% confidence interval is 0.00323. There are 2 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.162G>A	p.Lys54Lys	synonymous_variant	3/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.162G>A	p.Lys54Lys	synonymous_variant	3/11		NP_001308980.1
ADA	NM_001322050.2	c.-128G>A		5_prime_UTR_variant	3/11		NP_001308979.1
ADA	NR_136160.2	n.254G>A		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.162G>A	p.Lys54Lys	synonymous_variant	3/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.162G>A	p.Lys54Lys	synonymous_variant	3/9			ENSP00000512318.1
ADA	ENST00000695991.1	c.162G>A	p.Lys54Lys	synonymous_variant	3/8			ENSP00000512314.1
ADA	ENST00000696038.1	n.162G>A		non_coding_transcript_exon_variant	3/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00322 AC: 810 AN: 251454 Hom.: 2 AF XY: 0.00330 AC XY: 448 AN XY: 135920

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00353 AC: 5163 AN: 1461882 Hom.: 12 Cov.: 32 AF XY: 0.00357 AC XY: 2594 AN XY: 727242

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00204

Gnomad4 FIN exome AF: 0.00766

Gnomad4 NFE exome AF: 0.00390

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74494

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00338 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ADA: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2021

- -

ADA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.6
DANN	Benign	0.73

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: rs45557242; hg19: chr20-43257744;