20-44636286-C-T

Variant names:

• chr20-44636286-C-T
• rs394105
• NM_000022.4:c.36G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000022.4(ADA):​c.36G>A​(p.Val12Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,605,098 control chromosomes in the GnomAD database, including 798,115 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74032 hom., cov: 31)
  • Exomes 𝑓: 1.0 (724083 hom.)
• Consequence: ADA NM_000022.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.62
• Publications: 18 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 20-44636286-C-T is Benign according to our data. Variant chr20-44636286-C-T is described in ClinVar as Benign. ClinVar VariationId is 402340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.36G>A	p.Val12Val	splice_region_variant, synonymous_variant	Exon 2 of 12	ENST00000372874.9	NP_000013.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.36G>A	p.Val12Val	splice_region_variant, synonymous_variant	Exon 2 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.36G>A	p.Val12Val	splice_region_variant, synonymous_variant	Exon 2 of 9			ENSP00000512318.1
ADA	ENST00000695991.1	c.36G>A	p.Val12Val	splice_region_variant, synonymous_variant	Exon 2 of 8			ENSP00000512314.1
ADA	ENST00000696038.1	n.36G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.986 AC: 149997 AN: 152154 Hom.: 73976 Cov.: 31

Gnomad AFR AF: 0.950

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.987

GnomAD2 exomes AF: 0.996 AC: 238412 AN: 239298 AF XY: 0.997

Gnomad AFR exome AF: 0.947

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.998 AC: 1450438 AN: 1452826 Hom.: 724083 Cov.: 41 AF XY: 0.999 AC XY: 720807 AN XY: 721852

African (AFR) AF: 0.943 AC: 31446 AN: 33350

American (AMR) AF: 0.997 AC: 43320 AN: 43436

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25920 AN: 25920

East Asian (EAS) AF: 1.00 AC: 39618 AN: 39618

South Asian (SAS) AF: 1.00 AC: 84669 AN: 84686

European-Finnish (FIN) AF: 1.00 AC: 53052 AN: 53052

Middle Eastern (MID) AF: 0.997 AC: 5734 AN: 5754

European-Non Finnish (NFE) AF: 1.00 AC: 1106751 AN: 1106866

Other (OTH) AF: 0.996 AC: 59928 AN: 60144

GnomAD4 genome AF: 0.986 AC: 150112 AN: 152272 Hom.: 74032 Cov.: 31 AF XY: 0.986 AC XY: 73402 AN XY: 74448

African (AFR) AF: 0.950 AC: 39464 AN: 41524

American (AMR) AF: 0.996 AC: 15240 AN: 15302

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5176

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4816

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68033 AN: 68042

Other (OTH) AF: 0.987 AC: 2088 AN: 2116

Alfa AF: 0.993 Hom.: 42395

Bravo AF: 0.983

Asia WGS AF: 0.998 AC: 3470 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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 Benign:3

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -

Jan 09, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.56
DANN	Benign	0.58
PhyloP100		-2.6
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs394105; hg19: chr20-43264927;