20-44626579-T-C

Variant names:

• chr20-44626579-T-C
• rs11555566
• NM_000022.4:c.239A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The NM_000022.4:c.239A>G variant in ADA is a missense variant predicted to cause substitution of lysine by arginine at amino acid 80 (p.Lys80Arg). The Popmax filtering allele frequency of this variant in the gnomAD v2.1.1 database is 0.06430, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 (BA1). This variant has been observed in 551 homozygous individuals with no feature of SCID, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251993/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.059 (274 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2916 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: 3.06
• Publications: 27 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]

ADA Gene-Disease associations (from GenCC):

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for ADA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.239A>G	p.Lys80Arg	missense	Exon 4 of 12	NP_000013.2
	ADA	NM_001322051.2		c.239A>G	p.Lys80Arg	missense	Exon 4 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.-51A>G		5_prime_UTR	Exon 4 of 11	NP_001308979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.239A>G	p.Lys80Arg	missense	Exon 4 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.239A>G	p.Lys80Arg	missense	Exon 4 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.216+2470A>G		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8925 AN: 152170 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.0656

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0584

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0634

Gnomad OTH AF: 0.0636

GnomAD2 exomes AF: 0.0574 AC: 14437 AN: 251426 AF XY: 0.0587

Gnomad AFR exome AF: 0.0640

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.0827

Gnomad EAS exome AF: 0.00142

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0655

Gnomad OTH exome AF: 0.0642

GnomAD4 exome AF: 0.0602 AC: 87946 AN: 1461798 Hom.: 2916 Cov.: 32 AF XY: 0.0605 AC XY: 44028 AN XY: 727200

African (AFR) AF: 0.0700 AC: 2344 AN: 33480

American (AMR) AF: 0.0593 AC: 2654 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0805 AC: 2103 AN: 26134

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39690

South Asian (SAS) AF: 0.0591 AC: 5098 AN: 86254

European-Finnish (FIN) AF: 0.0421 AC: 2248 AN: 53406

Middle Eastern (MID) AF: 0.114 AC: 656 AN: 5736

European-Non Finnish (NFE) AF: 0.0619 AC: 68875 AN: 1111982

Other (OTH) AF: 0.0653 AC: 3943 AN: 60394

GnomAD4 genome AF: 0.0586 AC: 8928 AN: 152288 Hom.: 274 Cov.: 32 AF XY: 0.0571 AC XY: 4251 AN XY: 74468

African (AFR) AF: 0.0656 AC: 2726 AN: 41560

American (AMR) AF: 0.0476 AC: 728 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 293 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5172

South Asian (SAS) AF: 0.0585 AC: 282 AN: 4824

European-Finnish (FIN) AF: 0.0355 AC: 377 AN: 10624

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0634 AC: 4310 AN: 68014

Other (OTH) AF: 0.0634 AC: 134 AN: 2114

Alfa AF: 0.0631 Hom.: 760

Bravo AF: 0.0608

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0631 AC: 243

ESP6500AA AF: 0.0681 AC: 300

ESP6500EA AF: 0.0635 AC: 546

ExAC AF: 0.0588 AC: 7145

Asia WGS AF: 0.0380 AC: 130 AN: 3478

EpiCase AF: 0.0682

EpiControl AF: 0.0692

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	5	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (6)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.21	N
PhyloP100		3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.29
Sift	Benign	0.36	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.16
MPC		0.12
ClinPred		0.012	T
GERP RS		2.6
Varity_R		0.073
gMVP		0.54
Mutation Taster		=94/6	polymorphism (auto)

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: rs11555566; hg19: chr20-43255220; COSMIC: COSV65739876; COSMIC: COSV65739876;