chr20-44625602-G-A

Position:

• chr20-44625602-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_Moderate PM2 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000022.4:c.445C>T (p.Arg149Trp) variant in ADA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 149 (p.Arg149Trp). This variant has been reported in an individual with severe combined immunodeficiency and elevated pre-treatment erythrocyte dAXP (2pts, PMID:10200056) (PP4_Moderate). In experimental studies, the activity of this variant was reported as being 0.012% of wild-type activity (PMID:9758612) (PS3_Moderate). The highest subpopulation allele frequency 0.00009294 (2/21520) in African/African American population, which is lower than the ADA cutoff gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PP4_Moderate, PS3_Moderate (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA266014/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2 O:1
• Conservation: PhyloP100: 4.53

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 (HGNC:):

ACMG classification

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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.445C>T	p.Arg149Trp	missense_variant	5/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.445C>T	p.Arg149Trp	missense_variant	5/11		NP_001308980.1
ADA	NM_001322050.2	c.73+854C>T		intron_variant			NP_001308979.1
ADA	NR_136160.2	n.537C>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.445C>T	p.Arg149Trp	missense_variant	5/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-2524C>T		intron_variant				ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2672C>T		intron_variant				ENSP00000512314.1
ADA	ENST00000696038.1	n.*191C>T		non_coding_transcript_exon_variant	5/9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*191C>T		3_prime_UTR_variant	5/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000142 AC: 3 AN: 211354 Hom.: 0 AF XY: 0.0000264 AC XY: 3 AN XY: 113646

Gnomad AFR exome AF: 0.0000780

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000548

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1436750 Hom.: 0 Cov.: 31 AF XY: 0.0000126 AC XY: 9 AN XY: 712326

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.0000482

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2 Other: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:2 Uncertain:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 14, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 149 of the ADA protein (p.Arg149Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 10200056, 32888943). ClinVar contains an entry for this variant (Variation ID: 68264). 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 expected to disrupt ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). This variant disrupts the p.Arg149 amino acid residue in ADA. Other variant(s) that disrupt this residue have been observed in individuals with ADA-related conditions (PMID: 2166947), which suggests that this may be a clinically significant amino acid residue. 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. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Oct 10, 2023	The NM_000022.4:c.445C>T (p.Arg149Trp) variant in ADA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 149 (p.Arg149Trp). This variant has been reported in an individual with severe combined immunodeficiency and elevated pre-treatment erythrocyte dAXP (2pts, PMID: 10200056) (PP4_Moderate). In experimental studies, the activity of this variant was reported as being 0.012% of wild-type activity (PMID: 9758612) (PS3_Moderate). The highest subpopulation allele frequency 0.00009294 (2/21520) in African/African American population, which is lower than the ADA cutoff gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PP4_Moderate, PS3_Moderate (SCID VCEP specifications version 1.0). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.014	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.94		Loss of MoRF binding (P = 0.0536);Loss of MoRF binding (P = 0.0536);
MVP		0.94
MPC		0.46
ClinPred		0.85	D
GERP RS		3.5
Varity_R		0.94
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs121908733; hg19: chr20-43254243; COSMIC: COSV104684856; COSMIC: COSV104684856;