NM_000048.4:c.1079T>C

Variant names:

• chr7-66092022-T-C
• rs875989948
• NM_000048.4:c.1079T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000048.4(ASL):​c.1079T>C​(p.Met360Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M360V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 6.07
• 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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66092021-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1349828.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.7488 (below the threshold of 3.09). Trascript score misZ: 1.388 (below the threshold of 3.09). GenCC associations: The gene is linked to argininosuccinic aciduria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 7-66092022-T-C is Pathogenic according to our data. Variant chr7-66092022-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 226414.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.1079T>C	p.Met360Thr	missense_variant	Exon 15 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.1079T>C	p.Met360Thr	missense_variant	Exon 14 of 16		NP_001020114.1
ASL	NM_001024944.2	c.1019T>C	p.Met340Thr	missense_variant	Exon 13 of 15		NP_001020115.1
ASL	NM_001024946.2	c.1001T>C	p.Met334Thr	missense_variant	Exon 13 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.1079T>C	p.Met360Thr	missense_variant	Exon 15 of 17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.392T>C	p.Met131Thr	missense_variant	Exon 6 of 12	5		ENSP00000396527.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461370 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727006

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2 Uncertain:1

Oct 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 360 of the ASL protein (p.Met360Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (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: 226414). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASL function (PMID: 11747433). For these reasons, this variant has been classified as Pathogenic.

May 09, 2016

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 09, 2018

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
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.;D;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
LIST_S2	Benign	0.0	.;T;T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;M;.;.
PhyloP100		6.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;.
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Vest4		0.84
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.94
Mutation Taster		=0/100	disease causing

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: rs875989948; hg19: chr7-65557009;