7-66092828-T-G

Variant names:

• chr7-66092828-T-G
• rs932494060
• NM_000048.4:c.1311T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000048.4(ASL):​c.1311T>G​(p.Tyr437*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y437Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASL NM_000048.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0330
• Publications: 1 publications found

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

ENSG00000249319 (HGNC:):

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-66092828-T-G is Pathogenic according to our data. Variant chr7-66092828-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 556889.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.1311T>G	p.Tyr437*	stop_gained	Exon 17 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.1311T>G	p.Tyr437*	stop_gained	Exon 16 of 16		NP_001020114.1
ASL	NM_001024944.2	c.1251T>G	p.Tyr417*	stop_gained	Exon 15 of 15		NP_001020115.1
ASL	NM_001024946.2	c.1233T>G	p.Tyr411*	stop_gained	Exon 15 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.1311T>G	p.Tyr437*	stop_gained	Exon 17 of 17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.563+165T>G		intron_variant	Intron 7 of 11	5		ENSP00000396527.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2

Feb 26, 2018

Counsyl

Significance: Likely pathogenic

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.

Dec 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ASL protein in which other variant(s) (p.Arg456Trp) have been determined to be pathogenic (PMID: 17326097, 19703900, 24166829, 26843370). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 32410394). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr437*) in the ASL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the ASL protein.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;.;.;.
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.0	.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		0.033
PROVEAN	Benign	0.0	.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.
Vest4		0.87
GERP RS		-0.44
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs932494060; hg19: chr7-65557815;