rs765216

Variant names:

• chr20-44636218-T-C
• rs765216
• NM_000022.4:c.95+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000022.4(ADA):​c.95+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,607,710 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: ADA NM_000022.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.33
• 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]

ADA Gene-Disease associations (from GenCC):

• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-44636218-T-C is Benign according to our data. Variant chr20-44636218-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.003 (456/152230) while in subpopulation AFR AF = 0.0106 (439/41560). AF 95% confidence interval is 0.00975. There are 2 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.95+9A>G		intron_variant	Intron 2 of 11	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.95+9A>G		intron_variant	Intron 2 of 10		NP_001308980.1
ADA	NM_001322050.2	c.-195+9A>G		intron_variant	Intron 2 of 10		NP_001308979.1
ADA	NR_136160.2	n.187+9A>G		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.95+9A>G		intron_variant	Intron 2 of 11	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.95+9A>G		intron_variant	Intron 2 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.95+9A>G		intron_variant	Intron 2 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.95+9A>G		intron_variant	Intron 2 of 8			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152112 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000672 AC: 163 AN: 242694 AF XY: 0.000548

Gnomad AFR exome AF: 0.00998

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000913

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000251 AC: 366 AN: 1455480 Hom.: 1 Cov.: 29 AF XY: 0.000222 AC XY: 161 AN XY: 723716

African (AFR) AF: 0.00958 AC: 320 AN: 33388

American (AMR) AF: 0.000364 AC: 16 AN: 43946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5598

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108490

Other (OTH) AF: 0.000399 AC: 24 AN: 60142

GnomAD4 genome AF: 0.00300 AC: 456 AN: 152230 Hom.: 2 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74424

African (AFR) AF: 0.0106 AC: 439 AN: 41560

American (AMR) AF: 0.000654 AC: 10 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00343

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 24, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.12
DANN	Benign	0.52
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs765216; hg19: chr20-43264859;