20-44622851-C-T

Position:

chr20-44622851-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000022.4(ADA):c.758G>A(p.Arg253Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000904 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.131

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:

ADA (HGNC:):

ADA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25285906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4 linkuse as main transcript	c.758G>A	p.Arg253Gln	missense_variant	8/12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 linkuse as main transcript	c.686G>A	p.Arg229Gln	missense_variant	7/11		NP_001308980.1	F5GWI4
ADA	NM_001322050.2 linkuse as main transcript	c.353G>A	p.Arg118Gln	missense_variant	7/11		NP_001308979.1
ADA	NR_136160.2 linkuse as main transcript	n.850G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.758G>A	p.Arg253Gln	missense_variant	8/12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000695995.1 linkuse as main transcript	c.368G>A	p.Arg123Gln	missense_variant	5/9			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 linkuse as main transcript	c.296G>A	p.Arg99Gln	missense_variant	4/8			ENSP00000512314.1	A0A0S2Z3B9
ADA	ENST00000696038.1 linkuse as main transcript	n.*580G>A		non_coding_transcript_exon_variant	7/9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000696038.1 linkuse as main transcript	n.*580G>A		3_prime_UTR_variant	7/9			ENSP00000512344.1	A0A8Q3SJ57

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251496

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000665

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000171

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the ADA protein (p.Arg253Gln). This variant is present in population databases (rs148994526, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with ADA-related conditions. ClinVar contains an entry for this variant (Variation ID: 536185). 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. This variant disrupts the p.Arg253 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8258146, 9758612). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.12

CADD

Benign

4.9

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

D;D

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.85

D;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

0.0012

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.33

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.12

B;.

Vest4

0.35

MVP

0.93

MPC

0.20

ClinPred

0.051

GERP RS

-5.0

Varity_R

0.13

gMVP

0.65

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