dbSNP rs2228415: ADSL:p.Leu42Leu (chr22-40346682-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000026.4(ADSL):c.124C>T(p.Leu42Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.013 in 1,611,704 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L42L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0094 ( 9 hom., cov: 32)

Exomes 𝑓: 0.013 ( 154 hom. )

Consequence

ADSL
NM_000026.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.87

Publications

6 publications found

Variant links:

Genes affected

ADSL (HGNC:291): (adenylosuccinate lyase) The protein encoded by this gene belongs to the lyase 1 family. It is an essential enzyme involved in purine metabolism, and catalyzes two non-sequential reactions in the de novo purine biosynthetic pathway: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR) and the conversion of adenylosuccinate (S-AMP) to adenosine monophosphate (AMP). Mutations in this gene are associated with adenylosuccinase deficiency (ADSLD), a disorder marked with psychomotor retardation, epilepsy or autistic features. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ADSL Gene-Disease associations (from GenCC):

adenylosuccinate lyase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ADSL links:

ENSG00000284431 (HGNC:):

ENSG00000284431 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 22-40346682-C-T is Benign according to our data. Variant chr22-40346682-C-T is described in ClinVar as Benign. ClinVar VariationId is 128276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00935 (1425/152342) while in subpopulation NFE AF = 0.0151 (1028/68036). AF 95% confidence interval is 0.0143. There are 9 homozygotes in GnomAd4. There are 682 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000026.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADSL	NM_000026.4	MANE Select	c.124C>T	p.Leu42Leu	synonymous	Exon 1 of 13	NP_000017.1	X5D8S6
ADSL	NM_001410812.1		c.124C>T	p.Leu42Leu	synonymous	Exon 1 of 14	NP_001397741.1	A0A7P0Z472
ADSL	NM_001363840.3		c.124C>T	p.Leu42Leu	synonymous	Exon 1 of 14	NP_001350769.1	A0A1B0GWJ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADSL	ENST00000623063.3	TSL:1 MANE Select	c.124C>T	p.Leu42Leu	synonymous	Exon 1 of 13	ENSP00000485525.1	P30566-1
ADSL	ENST00000342312.9	TSL:1	c.124C>T	p.Leu42Leu	synonymous	Exon 1 of 12	ENSP00000341429.6	P30566-2
ADSL	ENST00000480775.3	TSL:1	n.124C>T		non_coding_transcript_exon	Exon 1 of 13	ENSP00000485462.2	A0A096LP92

Frequencies

GnomAD3 genomes

AF:

0.00935

AC:

1424

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00962

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00944

AC:

2303

AN:

243966

AF XY:

0.00934

show subpopulations

Gnomad AFR exome

AF:

0.00226

Gnomad AMR exome

AF:

0.00870

Gnomad ASJ exome

AF:

0.00473

Gnomad EAS exome

AF:

0.0000549

Gnomad FIN exome

AF:

0.0125

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0134

AC:

19586

AN:

1459362

Hom.:

154

Cov.:

AF XY:

0.0130

AC XY:

9438

AN XY:

726052

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33454

American (AMR)

AF:

0.00908

AC:

405

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00552

AC:

144

AN:

26094

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39662

South Asian (SAS)

AF:

0.000244

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.0122

AC:

633

AN:

51970

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0159

AC:

17646

AN:

1111478

Other (OTH)

AF:

0.0108

AC:

650

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1027

2054

3080

4107

5134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

664

1328

1992

2656

3320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00935

AC:

1425

AN:

152342

Hom.:

Cov.:

AF XY:

0.00915

AC XY:

682

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41582

American (AMR)

AF:

0.00961

AC:

147

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0104

AC:

111

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1028

AN:

68036

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00956

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0147

EpiControl

AF:

0.0158

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Adenylosuccinate lyase deficiency (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

4.9

PromoterAI

0.052

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over