rs1555844120

Positions:

• chr20-44622873-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.736C>T (p.Gln246Ter)(NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant is absent in gnomAD v4 (PM2_Supporting). One patient (U444) was found homozygous for this mutation (PMID:17185467,PM3_Supporting).Based on the above evidence, this variant can be classified as pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PVS1_Met,PM2_Supporting,PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409120239/MONDO:0007064/114

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADA ENST00000372874.9 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 0.00400

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]

PKIG (HGNC:9019): (cAMP-dependent protein kinase inhibitor gamma) This gene encodes a member of the protein kinase inhibitor family. Studies of a similar protein in mice suggest that this protein acts as a potent competitive cAMP-dependent protein kinase inhibitor, and is a predominant form of inhibitor in various tissues. The encoded protein may be involved in osteogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.736C>T	p.Gln246Ter	stop_gained	8/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.664C>T	p.Gln222Ter	stop_gained	7/11		NP_001308980.1
ADA	NM_001322050.2	c.331C>T	p.Gln111Ter	stop_gained	7/11		NP_001308979.1
ADA	NR_136160.2	n.828C>T		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.736C>T	p.Gln246Ter	stop_gained	8/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2022	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 24, 2024	The c.736C>T (p.Gln246Ter)(NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant is absent in gnomAD v4 (PM2_Supporting). One patient (U444) was found homozygous for this mutation (PMID: 17185467,PM3_Supporting).Based on the above evidence, this variant can be classified as pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PVS1_Met,PM2_Supporting,PM3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2021	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln246*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 549915). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 31589898). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Benign	0.95
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.14	N
MutationTaster	Benign	1.0	A;A;N;N
Vest4		0.93
GERP RS		-4.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555844120; hg19: chr20-43251514;