rs1057520217

Variant names:

• chr20-44651601-G-A
• rs1057520217
• NM_000022.4:c.7C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000022.4(ADA):​c.7C>T​(p.Gln3*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ADA NM_000022.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.97
• Publications: 5 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 116 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-44651601-G-A is Pathogenic according to our data. Variant chr20-44651601-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 377441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 12	NP_000013.2
	ADA	NM_001322051.2		c.7C>T	p.Gln3*	stop_gained	Exon 1 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.-283C>T		5_prime_UTR	Exon 1 of 11	NP_001308979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.7C>T	p.Gln3*	stop_gained	Exon 1 of 9	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 137408 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386272 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 685512

African (AFR) AF: 0.0000324 AC: 1 AN: 30832

American (AMR) AF: 0.00 AC: 0 AN: 36952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24998

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4318

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081840

Other (OTH) AF: 0.00 AC: 0 AN: 57694

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (4)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.77	D
PhyloP100		2.0
Vest4		0.56
GERP RS		3.4
PromoterAI		0.18	Neutral
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1057520217; hg19: chr20-43280242;