Genetic Variant ADSL:p.Arg190Leu (chr22-40358950-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000026.4(ADSL):c.569G>T(p.Arg190Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADSL
NM_000026.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.61

Publications

0 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ADSL links:

ENSG00000284431 (HGNC:):

ENSG00000284431 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000026.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-40358949-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2725586.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADSL	NM_000026.4 link	c.569G>T	p.Arg190Leu	missense_variant	Exon 5 of 13	ENST00000623063.3	NP_000017.1	P30566-1X5D8S6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADSL	ENST00000623063.3 link	c.569G>T	p.Arg190Leu	missense_variant	Exon 5 of 13	1	NM_000026.4	ENSP00000485525.1	P30566-1
ENSG00000284431	ENST00000639722.1 link	n.*265G>T		non_coding_transcript_exon_variant	Exon 4 of 31	5		ENSP00000492828.1	A0A1W2PRX2
ENSG00000284431	ENST00000639722.1 link	n.*265G>T		3_prime_UTR_variant	Exon 4 of 31	5		ENSP00000492828.1	A0A1W2PRX2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.070

T;D;.;T;T;T;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.64

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.1

.;L;L;.;.;.;.;.

PhyloP100

3.6

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-4.9

.;.;D;.;.;.;.;.

REVEL

Uncertain

0.58

Sift

Benign

0.27

.;.;T;.;.;.;.;.

Sift4G

Benign

0.61

T;T;T;.;T;T;.;.

Polyphen

0.0020, 0.025

.;B;B;.;.;.;.;.

Vest4

0.71, 0.65, 0.67

MutPred

0.67

.;.;.;.;Loss of methylation at R204 (P = 0.0457);.;.;.;

MVP

0.93

MPC

0.50

ClinPred

0.68

GERP RS

2.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.81

gMVP

0.95

Mutation Taster

=35/65

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over