NM_000048.4:c.578G>A

Variant names:

• chr7-66086797-G-A
• rs373697663
• NM_000048.4:c.578G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000048.4(ASL):​c.578G>A​(p.Arg193Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000699 in 1,587,274 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000712578: "In vitro functional studies provide some evidence that this variant may impact protein function (Hu 2014)"" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R193W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.87
• Publications: 5 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: Orphanet, Myriad Women’s Health, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000712578: "In vitro functional studies provide some evidence that this variant may impact protein function (Hu 2014)"; SCV001222226: Experimental studies have shown that this missense change affects ASL function (PMID: 25778938).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66086796-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 553200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.895
• PP5: Variant 7-66086797-G-A is Pathogenic according to our data. Variant chr7-66086797-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000048.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	NM_000048.4	MANE Select	c.578G>A	p.Arg193Gln	missense	Exon 8 of 17	NP_000039.2
	ASL	NM_001024943.2		c.578G>A	p.Arg193Gln	missense	Exon 7 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.578G>A	p.Arg193Gln	missense	Exon 7 of 15	NP_001020115.1	P04424-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	ENST00000304874.14	TSL:1 MANE Select	c.578G>A	p.Arg193Gln	missense	Exon 8 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.578G>A	p.Arg193Gln	missense	Exon 7 of 16	ENSP00000378741.3	P04424-1
	ASL	ENST00000906815.1		c.671G>A	p.Arg224Gln	missense	Exon 9 of 18	ENSP00000576874.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000198 AC: 4 AN: 201534 AF XY: 0.0000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000114

Gnomad OTH exome AF: 0.000193

GnomAD4 exome AF: 0.0000732 AC: 105 AN: 1435128 Hom.: 0 Cov.: 32 AF XY: 0.0000745 AC XY: 53 AN XY: 711744

African (AFR) AF: 0.0000303 AC: 1 AN: 33050

American (AMR) AF: 0.00 AC: 0 AN: 39950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25560

East Asian (EAS) AF: 0.00 AC: 0 AN: 38414

South Asian (SAS) AF: 0.0000722 AC: 6 AN: 83130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000846 AC: 93 AN: 1099544

Other (OTH) AF: 0.0000842 AC: 5 AN: 59386

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000750 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Argininosuccinate lyase deficiency (7)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.94
MVP		0.99
MPC		0.90
ClinPred		0.87	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.91
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.050		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: rs373697663; hg19: chr7-65551784; COSMIC: COSV59187938; COSMIC: COSV59187938;