rs61737144

Variant names:

• chr20-44625657-C-T
• rs61737144
• NM_000022.4:c.390G>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.390G>A​(p.Val130Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,570,220 control chromosomes in the GnomAD database, including 1,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (141 hom., cov: 32)
  • Exomes 𝑓: 0.034 (871 hom.)
• Consequence: ADA NM_000022.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.08
• Publications: 7 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-44625657-C-T is Benign according to our data. Variant chr20-44625657-C-T is described in ClinVar as Benign. ClinVar VariationId is 35653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

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.390G>A	p.Val130Val	synonymous	Exon 5 of 12	NP_000013.2
	ADA	NM_001322051.2		c.390G>A	p.Val130Val	synonymous	Exon 5 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.73+799G>A		intron	N/A	NP_001308979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.390G>A	p.Val130Val	synonymous	Exon 5 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.390G>A	p.Val130Val	synonymous	Exon 5 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.217-2579G>A		intron	N/A	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes AF: 0.0398 AC: 6056 AN: 152178 Hom.: 141 Cov.: 32

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0350

Gnomad OTH AF: 0.0383

GnomAD2 exomes AF: 0.0301 AC: 5382 AN: 179032 AF XY: 0.0296

Gnomad AFR exome AF: 0.0618

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0452

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0335

GnomAD4 exome AF: 0.0337 AC: 47801 AN: 1417924 Hom.: 871 Cov.: 32 AF XY: 0.0331 AC XY: 23236 AN XY: 701200

African (AFR) AF: 0.0593 AC: 1932 AN: 32600

American (AMR) AF: 0.0175 AC: 677 AN: 38580

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 1049 AN: 25284

East Asian (EAS) AF: 0.000133 AC: 5 AN: 37598

South Asian (SAS) AF: 0.0171 AC: 1381 AN: 80666

European-Finnish (FIN) AF: 0.0429 AC: 2157 AN: 50228

Middle Eastern (MID) AF: 0.0316 AC: 172 AN: 5444

European-Non Finnish (NFE) AF: 0.0352 AC: 38317 AN: 1088822

Other (OTH) AF: 0.0360 AC: 2111 AN: 58702

GnomAD4 genome AF: 0.0398 AC: 6063 AN: 152296 Hom.: 141 Cov.: 32 AF XY: 0.0390 AC XY: 2907 AN XY: 74470

African (AFR) AF: 0.0582 AC: 2417 AN: 41558

American (AMR) AF: 0.0309 AC: 473 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4826

European-Finnish (FIN) AF: 0.0449 AC: 477 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0350 AC: 2382 AN: 68014

Other (OTH) AF: 0.0379 AC: 80 AN: 2112

Alfa AF: 0.0373 Hom.: 82

Bravo AF: 0.0394

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.8
DANN	Benign	0.76
PhyloP100		1.1
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61737144; hg19: chr20-43254298; COSMIC: COSV65740318; COSMIC: COSV65740318;