20-44646360-T-C

Variant names:

• chr20-44646360-T-C
• rs2299686
• NM_000022.4:c.33+5215A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000022.4(ADA):​c.33+5215A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,090 control chromosomes in the GnomAD database, including 22,063 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (22063 hom., cov: 33)
• Consequence: ADA NM_000022.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.177
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.33+5215A>G		intron_variant	Intron 1 of 11	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.33+5215A>G		intron_variant	Intron 1 of 10		NP_001308980.1
ADA	NM_001322050.2	c.-257+5215A>G		intron_variant	Intron 1 of 10		NP_001308979.1
ADA	NR_136160.2	n.125+5215A>G		intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.33+5215A>G		intron_variant	Intron 1 of 11	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.33+5215A>G		intron_variant	Intron 1 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.33+5215A>G		intron_variant	Intron 1 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.33+5215A>G		intron_variant	Intron 1 of 8			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80461 AN: 151972 Hom.: 22050 Cov.: 33

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.546

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.529 AC: 80513 AN: 152090 Hom.: 22063 Cov.: 33 AF XY: 0.537 AC XY: 39903 AN XY: 74372

African (AFR) AF: 0.380 AC: 15773 AN: 41474

American (AMR) AF: 0.521 AC: 7967 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2306 AN: 3472

East Asian (EAS) AF: 0.682 AC: 3517 AN: 5158

South Asian (SAS) AF: 0.643 AC: 3102 AN: 4824

European-Finnish (FIN) AF: 0.646 AC: 6841 AN: 10588

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39156 AN: 67980

Other (OTH) AF: 0.547 AC: 1154 AN: 2110

Alfa AF: 0.564 Hom.: 78938

Bravo AF: 0.514

Asia WGS AF: 0.653 AC: 2271 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.87
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs2299686; hg19: chr20-43275001;