rs121908718

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_SupportingPP4_ModeratePM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The c.890C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause the substitution of Proline by Leucine at amino acid 297 (p.Pro297Leu).The highest population minor allele frequency in gnomAD v4 is 0.000008350 (2/44896 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous was reported.This variant was described in at least one patient in the literature, who presents *Reduced ADA enzyme activity in patient cells (1pt); *Reported also reported "a definite increase in intracellular metabolites" (dAdo nucleotides), (2 pts); *SCID gene panel or exome/genome sequencing conducted (0.5pt). Total 3.5 points, PP4_Moderate (PMID:34975878).The variant expression in E. Coli falls into our activity Group III (Dr. Hershfield - internal communication). PS3 is met at the Supporting level of evidence.In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Moderate, and PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9871472/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ADA
ENST00000372874.9 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 6.50

Variant links:

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 links:

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]

PKIG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS3

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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADA	NM_000022.4 linkuse as main transcript	c.890C>T	p.Pro297Leu	missense_variant	10/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2 linkuse as main transcript	c.818C>T	p.Pro273Leu	missense_variant	9/11		NP_001308980.1
ADA	NM_001322050.2 linkuse as main transcript	c.485C>T	p.Pro162Leu	missense_variant	9/11		NP_001308979.1
ADA	NR_136160.2 linkuse as main transcript	n.917C>T		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.890C>T	p.Pro297Leu	missense_variant	10/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251492

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	The c.890C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause the substitution of Proline by Leucine at amino acid 297 (p.Pro297Leu). The highest population minor allele frequency in gnomAD v4 is 0.000008350 (2/44896 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous was reported. This variant was described in at least one patient in the literature, who presents Reduced ADA enzyme activity in patient cells (1pt); Reported also reported "a definite increase in intracellular metabolites" (dAdo nucleotides), (2 pts); *SCID gene panel or exome/genome sequencing conducted (0.5pt). Total 3.5 points, PP4_Moderate (PMID: 34975878). The variant expression in E. Coli falls into our activity Group III (Dr. Hershfield - internal communication). PS3 is met at the Supporting level of evidence. In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Moderate, and PS3_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 03, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro297 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2166947, 2783588). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADA protein function. ClinVar contains an entry for this variant (Variation ID: 1505857). This missense change has been observed in individual(s) with clinical features of ADA-related conditions (PMID: 34975878). This variant is present in population databases (rs121908718, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 297 of the ADA protein (p.Pro297Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.89

MutPred

0.92

Loss of phosphorylation at T294 (P = 0.1147);.;

MVP

0.97

MPC

0.61

ClinPred

1.0

GERP RS

5.0

Varity_R

0.90

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over