NM_000048.4:c.918+5G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000048.4(ASL):​c.918+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000048 in 1,459,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ASL
NM_000048.4 splice_region, intron

Scores

1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.99

Publications

1 publications found
Variant links:
Genes affected
ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
ASL Gene-Disease associations (from GenCC):
  • argininosuccinic aciduria
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 7-66089180-G-A is Pathogenic according to our data. Variant chr7-66089180-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 554215.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASLNM_000048.4 linkc.918+5G>A splice_region_variant, intron_variant Intron 12 of 16 ENST00000304874.14 NP_000039.2 P04424-1A0A024RDL8
ASLNM_001024943.2 linkc.918+5G>A splice_region_variant, intron_variant Intron 11 of 15 NP_001020114.1 P04424-1A0A024RDL8
ASLNM_001024944.2 linkc.918+5G>A splice_region_variant, intron_variant Intron 11 of 14 NP_001020115.1 P04424-2
ASLNM_001024946.2 linkc.840+5G>A splice_region_variant, intron_variant Intron 10 of 14 NP_001020117.1 A0A0S2Z316

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASLENST00000304874.14 linkc.918+5G>A splice_region_variant, intron_variant Intron 12 of 16 1 NM_000048.4 ENSP00000307188.9 P04424-1
ENSG00000249319ENST00000450043.2 linkc.231+5G>A splice_region_variant, intron_variant Intron 3 of 11 5 ENSP00000396527.2 H7C0S8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000160
AC:
4
AN:
249232
AF XY:
0.0000295
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1459392
Hom.:
0
Cov.:
35
AF XY:
0.00000689
AC XY:
5
AN XY:
726126
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33422
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26108
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39690
South Asian (SAS)
AF:
0.0000464
AC:
4
AN:
86214
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53174
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5752
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1109992
Other (OTH)
AF:
0.00
AC:
0
AN:
60324
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.454
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:1Uncertain:1
Aug 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change falls in intron 12 of the ASL gene. It does not directly change the encoded amino acid sequence of the ASL protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs781331391, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of argininosuccinate lyase deficiency (PMID: 24166829; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554215). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 29, 2017
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.17
CADD
Benign
23
DANN
Uncertain
0.98
PhyloP100
4.0
PromoterAI
-0.015
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Mutation Taster
=2/98
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.85
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.32
Position offset: -19
DS_DL_spliceai
0.85
Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs781331391; hg19: chr7-65554167; API