chr7-66086764-G-A

Variant names:

• chr7-66086764-G-A
• rs751590073
• NM_000048.4:c.545G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000048.4(ASL):​c.545G>A​(p.Arg182Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,603,044 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: "SCV000538014: Functional studies using a yeast complementation assay conclude the Arg182Gln variant is unable to complement relative to controls (Trevisson et al., 2009)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R182G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.81
• Publications: 0 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000538014: Functional studies using a yeast complementation assay conclude the Arg182Gln variant is unable to complement relative to controls (Trevisson et al., 2009).; SCV000829269: Experimental studies have shown that this missense change affects ASL function (PMID: 19703900).
• PM1: In a hotspot region, there are 5 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 chr7-66086763-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2735029.
• 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, 0.977
• PP5: Variant 7-66086764-G-A is Pathogenic according to our data. Variant chr7-66086764-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203613.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.545G>A	p.Arg182Gln	missense	Exon 8 of 17	NP_000039.2
	ASL	NM_001024943.2		c.545G>A	p.Arg182Gln	missense	Exon 7 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.545G>A	p.Arg182Gln	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.545G>A	p.Arg182Gln	missense	Exon 8 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.545G>A	p.Arg182Gln	missense	Exon 7 of 16	ENSP00000378741.3	P04424-1
	ASL	ENST00000906815.1		c.638G>A	p.Arg213Gln	missense	Exon 9 of 18	ENSP00000576874.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000220 AC: 5 AN: 227286 AF XY: 0.0000405

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: 0.0000493

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000365 AC: 53 AN: 1450900 Hom.: 0 Cov.: 32 AF XY: 0.0000444 AC XY: 32 AN XY: 721112

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 42718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25848

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39266

South Asian (SAS) AF: 0.00 AC: 0 AN: 84934

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000461 AC: 51 AN: 1107384

Other (OTH) AF: 0.00 AC: 0 AN: 59988

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000326 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000578 AC: 7

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Argininosuccinate lyase deficiency (9)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.91
Sift	Benign	0.13	T
Sift4G	Uncertain	0.056	T
Polyphen		0.99	D
Vest4		0.96
MutPred		0.90		Loss of MoRF binding (P = 0.0241)
MVP		0.99
MPC		0.62
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs751590073; hg19: chr7-65551751;