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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 11		NP_001308980.1
ADA	NR_136160.2	n.99C>T		non_coding_transcript_exon_variant	Exon 1 of 11
ADA	NM_001322050.2	c.-283C>T		5_prime_UTR_variant	Exon 1 of 11		NP_001308979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 9			ENSP00000512318.1
ADA	ENST00000695991.1	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 8			ENSP00000512314.1
ADA	ENST00000696038.1	n.7C>T		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512344.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:4

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gain variant c.7C>T (p.Gln3Ter) in ADA gene has been reported previously in homozygous state in multiple individuals affected with ADA related disorder (Pajno R, et al. 2020; Sanchez JJ et al. 2007). The p.Gln3Ter variant has allele frequency 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.7C>T in ADA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in ADA are known to be pathogenic (Baffelli R et al. 2015). For these reasons, this variant has been classified as Pathogenic. -

Jul 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 377441). This premature translational stop signal has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8589684, 25875700, 25954555). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln3*) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). -

Jun 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jan 28, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8589684, 17181544, 25875700, 32307643, 33726816, 32098966, 31858364, 26255240) -

Computational scores

Source: dbNSFP v4.3

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;