rs1555844120

Variant names:

• chr20-44622873-G-A
• rs1555844120
• NM_000022.4:c.736C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM3_Supporting PVS1 PM2_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 NM_000022.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 0.00400
• Publications: 0 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]

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

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.736C>T	p.Gln246*	stop_gained	Exon 8 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.664C>T	p.Gln222*	stop_gained	Exon 7 of 11		NP_001308980.1
ADA	NM_001322050.2	c.331C>T	p.Gln111*	stop_gained	Exon 7 of 11		NP_001308979.1
ADA	NR_136160.2	n.828C>T		non_coding_transcript_exon_variant	Exon 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.736C>T	p.Gln246*	stop_gained	Exon 8 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.346C>T	p.Gln116*	stop_gained	Exon 5 of 9			ENSP00000512318.1
ADA	ENST00000695991.1	c.274C>T	p.Gln92*	stop_gained	Exon 4 of 8			ENSP00000512314.1
ADA	ENST00000696038.1	n.*558C>T		non_coding_transcript_exon_variant	Exon 7 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*558C>T		3_prime_UTR_variant	Exon 7 of 9			ENSP00000512344.1

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

Sep 27, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 31589898). 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). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 549915). For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 24, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.0040
Vest4		0.93
GERP RS		-4.1
Mutation Taster		=2/198	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: rs1555844120; hg19: chr20-43251514;