chr20-44625645-G-A

Position:

chr20-44625645-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS2_SupportingBP7BS1

This summary comes from the ClinGen Evidence Repository: The c.402C>T (p.Gly134=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003095 (89/19874 alleles) in African/African American population, which is higher than the ClinGen SCID VCEP threshold (>0.00161) for BS1, and therefore meets this criterion (BS1). In the gnomAD v2.1.1 database, this variant has been observed in 1 homozygous individual with no features of SCID, a condition with full penetrance at an early age. BS2_supporting is met.In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BS1, BP7, and BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9871679/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 3 hom. )

Consequence

ADA
NM_000022.4 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 2.39

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP7

BS1

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADA	NM_000022.4 linkuse as main transcript	c.402C>T	p.Gly134=	synonymous_variant	5/12	ENST00000372874.9
ADA	NM_001322051.2 linkuse as main transcript	c.402C>T	p.Gly134=	synonymous_variant	5/11
ADA	NM_001322050.2 linkuse as main transcript	c.73+811C>T		intron_variant
ADA	NR_136160.2 linkuse as main transcript	n.494C>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA	ENST00000372874.9 linkuse as main transcript	c.402C>T	p.Gly134=	synonymous_variant	5/12	1	NM_000022.4	P4

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00473

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000326

AC:

AN:

186922

Hom.:

AF XY:

0.000220

AC XY:

AN XY:

99942

show subpopulations

Gnomad AFR exome

AF:

0.00403

Gnomad AMR exome

AF:

0.000533

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000406

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

193

AN:

1423336

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

704366

show subpopulations

Gnomad4 AFR exome

AF:

0.00439

Gnomad4 AMR exome

AF:

0.000635

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000246

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000374

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152314

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00471

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000642

Hom.:

Bravo

AF:

0.00148

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:5

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.402C>T (p.Gly134=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003095 (89/19874 alleles) in African/African American population, which is higher than the ClinGen SCID VCEP threshold (>0.00161) for BS1, and therefore meets this criterion (BS1). In the gnomAD v2.1.1 database, this variant has been observed in 1 homozygous individual with no features of SCID, a condition with full penetrance at an early age. BS2_supporting is met. In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BS1, BP7, and BS2_Supporting. -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 24, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 26, 2022	- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ADA p.Gly134Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs146921882) and ClinVar (classified as benign by Invitae for severe combined immunodeficiency due to ADA deficiency). The variant was also identified in control databases in 106 of 218308 chromosomes (1 homozygous) at a frequency of 0.000486 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 89 of 19874 chromosomes (freq: 0.004478), Latino in 16 of 29004 chromosomes (freq: 0.000552) and South Asian in 1 of 24660 chromosomes (freq: 0.000041), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) or Other populations. The p.Gly134Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

ADA-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

9.4

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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