rs406383

Variant names:

• chr20-44642751-C-G
• rs406383
• NM_000022.4:c.34-6463G>C

Your query was ambiguous. Multiple possible variants found:

• chr20-44642751-C-G
• chr20-44642751-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000022.4(ADA):​c.34-6463G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,010 control chromosomes in the GnomAD database, including 3,173 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3173 hom., cov: 32)
• Consequence: ADA NM_000022.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.959
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.34-6463G>C		intron_variant	Intron 1 of 11	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.34-6463G>C		intron_variant	Intron 1 of 10		NP_001308980.1
ADA	NM_001322050.2	c.-256-6463G>C		intron_variant	Intron 1 of 10		NP_001308979.1
ADA	NR_136160.2	n.126-6463G>C		intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.34-6463G>C		intron_variant	Intron 1 of 11	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.34-6463G>C		intron_variant	Intron 1 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.34-6463G>C		intron_variant	Intron 1 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.34-6463G>C		intron_variant	Intron 1 of 8			ENSP00000512344.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27735 AN: 151892 Hom.: 3172 Cov.: 32

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.189

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.182 AC: 27737 AN: 152010 Hom.: 3173 Cov.: 32 AF XY: 0.183 AC XY: 13581 AN XY: 74282

African (AFR) AF: 0.0507 AC: 2104 AN: 41508

American (AMR) AF: 0.285 AC: 4356 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 469 AN: 3464

East Asian (EAS) AF: 0.183 AC: 945 AN: 5154

South Asian (SAS) AF: 0.204 AC: 981 AN: 4808

European-Finnish (FIN) AF: 0.217 AC: 2290 AN: 10548

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15940 AN: 67952

Other (OTH) AF: 0.191 AC: 403 AN: 2108

Alfa AF: 0.0983 Hom.: 171

Bravo AF: 0.183

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.42
DANN	Benign	0.50
PhyloP100		-0.96
Mutation Taster		=100/0	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: rs406383; hg19: chr20-43271392;