rs1329070853

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_000048.4(ASL):c.1045_1062+7delGTCATCTCTACGCTGCAGGCAAGAC(p.Val349_Gln354del) variant causes a splice donor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,486 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V349V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASL
NM_000048.4 splice_donor, conservative_inframe_deletion, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.41

Publications

0 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

ASL links:

ENSG00000249319 (HGNC:):

ENSG00000249319 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.060215052 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of -30, new splice context is: cagGTggcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 7-66089676-GCGTCATCTCTACGCTGCAGGCAAGA-G is Pathogenic according to our data. Variant chr7-66089676-GCGTCATCTCTACGCTGCAGGCAAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 529426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4 link	c.1045_1062+7delGTCATCTCTACGCTGCAGGCAAGAC	p.Val349_Gln354del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 14 of 17	ENST00000304874.14	NP_000039.2	P04424-1A0A024RDL8
ASL	NM_001024943.2 link	c.1045_1062+7delGTCATCTCTACGCTGCAGGCAAGAC	p.Val349_Gln354del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 13 of 16		NP_001020114.1	P04424-1A0A024RDL8
ASL	NM_001024944.2 link	c.985_1002+7delGTCATCTCTACGCTGCAGGCAAGAC	p.Val329_Gln334del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 15		NP_001020115.1	P04424-2
ASL	NM_001024946.2 link	c.967_984+7delGTCATCTCTACGCTGCAGGCAAGAC	p.Val323_Gln328del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 15		NP_001020117.1	A0A0S2Z316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14 link	c.1044_1062+6delCGTCATCTCTACGCTGCAGGCAAGA	p.Val349LysfsTer68	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 14 of 17	1	NM_000048.4	ENSP00000307188.9		P04424-1
ENSG00000249319	ENST00000450043.2 link	c.357_375+6delCGTCATCTCTACGCTGCAGGCAAGA	p.Val120LysfsTer78	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 12	5		ENSP00000396527.2		H7C0S8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461302

Hom.:

AF XY:

0.00

AC XY:

AN XY:

726964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111758

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Argininosuccinate lyase deficiency

Pathogenic:2

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant results in the deletion of part of exon 14 (c.1045_1062+7del) of the ASL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with argininosuccinate lyase deficiency (PMID: 16941645; Invitae). ClinVar contains an entry for this variant (Variation ID: 529426). For these reasons, this variant has been classified as Pathogenic. -

Apr 27, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.4

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over