rs139350872

Positions:

• chr20-44636261-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000022.4(ADA):​c.61T>G​(p.Ser21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,610,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.713

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 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=0.17612821).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.61T>G	p.Ser21Ala	missense_variant	2/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.61T>G	p.Ser21Ala	missense_variant	2/11		NP_001308980.1
ADA	NM_001322050.2	c.-229T>G		5_prime_UTR_variant	2/11		NP_001308979.1
ADA	NR_136160.2	n.153T>G		non_coding_transcript_exon_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.61T>G	p.Ser21Ala	missense_variant	2/12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.61T>G	p.Ser21Ala	missense_variant	2/9			ENSP00000512318.1
ADA	ENST00000695991.1	c.61T>G	p.Ser21Ala	missense_variant	2/8			ENSP00000512314.1
ADA	ENST00000696038.1	n.61T>G		non_coding_transcript_exon_variant	2/9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

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: 0.0000205 AC: 5 AN: 244092 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131880

Gnomad AFR exome AF: 0.000325

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1457924 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 724874

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74324

Gnomad4 AFR AF: 0.000193

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: 0.0000579 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

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	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This sequence change replaces serine with alanine at codon 21 of the ADA protein (p.Ser21Ala). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and alanine. This variant is present in population databases (rs139350872, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with ADA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	4.1
DANN	Benign	0.25
DEOGEN2	Uncertain	0.58	D;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.54	N;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.0	N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.35
MVP		0.82
MPC		0.12
ClinPred		0.0098	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.081
gMVP		0.74

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

Other links and lift over

dbSNP: rs139350872; hg19: chr20-43264902;