20-44634715-C-T

Variant names:

• chr20-44634715-C-T
• rs447833
• NM_000022.4:c.95+1512G>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.95+1512G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 152,122 control chromosomes in the GnomAD database, including 31,301 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 0.63 (31301 hom., cov: 34)
• Consequence: ADA NM_000022.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.06
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.709 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.95+1512G>A		intron	N/A	NP_000013.2
	ADA	NM_001322051.2		c.95+1512G>A		intron	N/A	NP_001308980.1
	ADA	NM_001322050.2		c.-195+1512G>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.95+1512G>A		intron	N/A	ENSP00000361965.4
	ADA	ENST00000537820.2	TSL:1	c.95+1512G>A		intron	N/A	ENSP00000441818.1
	ADA	ENST00000695995.1		c.95+1512G>A		intron	N/A	ENSP00000512318.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96112 AN: 152004 Hom.: 31283 Cov.: 34

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.722

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.714

Gnomad OTH AF: 0.655

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

GnomAD4 genome AF: 0.632 AC: 96162 AN: 152122 Hom.: 31301 Cov.: 34 AF XY: 0.632 AC XY: 46970 AN XY: 74352

African (AFR) AF: 0.475 AC: 19712 AN: 41482

American (AMR) AF: 0.603 AC: 9213 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2225 AN: 3468

East Asian (EAS) AF: 0.690 AC: 3573 AN: 5180

South Asian (SAS) AF: 0.640 AC: 3087 AN: 4826

European-Finnish (FIN) AF: 0.722 AC: 7635 AN: 10582

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.714 AC: 48534 AN: 67984

Other (OTH) AF: 0.653 AC: 1377 AN: 2110

Alfa AF: 0.683 Hom.: 64712

Bravo AF: 0.615

Asia WGS AF: 0.636 AC: 2213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.022
DANN	Benign	0.55
PhyloP100		-3.1
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: rs447833; hg19: chr20-43263356;