NM_000022.4:c.34-6173C>A

Variant names:

• chr20-44642461-G-T
• rs452159
• NM_000022.4:c.34-6173C>A

Variant summary

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

The NM_000022.4(ADA):​c.34-6173C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,004 control chromosomes in the GnomAD database, including 6,259 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 0.28 (6259 hom., cov: 32)
• Consequence: ADA NM_000022.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.41
• Publications: 12 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.34-6173C>A		intron	N/A	NP_000013.2
	ADA	NM_001322051.2		c.34-6173C>A		intron	N/A	NP_001308980.1
	ADA	NM_001322050.2		c.-256-6173C>A		intron	N/A	NP_001308979.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.34-6173C>A		intron	N/A	ENSP00000361965.4
	ADA	ENST00000537820.2	TSL:1	c.34-6173C>A		intron	N/A	ENSP00000441818.1
	ADA	ENST00000695995.1		c.34-6173C>A		intron	N/A	ENSP00000512318.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42245 AN: 151886 Hom.: 6250 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.264

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

GnomAD4 genome AF: 0.278 AC: 42302 AN: 152004 Hom.: 6259 Cov.: 32 AF XY: 0.276 AC XY: 20485 AN XY: 74290

African (AFR) AF: 0.339 AC: 14071 AN: 41450

American (AMR) AF: 0.235 AC: 3589 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2235 AN: 5160

South Asian (SAS) AF: 0.226 AC: 1088 AN: 4812

European-Finnish (FIN) AF: 0.244 AC: 2576 AN: 10570

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17388 AN: 67954

Other (OTH) AF: 0.266 AC: 560 AN: 2104

Alfa AF: 0.256 Hom.: 6709

Bravo AF: 0.282

Asia WGS AF: 0.341 AC: 1181 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.15
DANN	Benign	0.67
PhyloP100		-4.4
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: rs452159; hg19: chr20-43271102;