rs145138923

Variant names:

• chr7-66081825-G-A
• rs145138923
• NM_000048.4:c.35G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-66081825-G-A
• chr7-66081825-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM5 PP2 PP5_Very_Strong

The NM_000048.4(ASL):​c.35G>A​(p.Arg12Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,768 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000238706: Functional expression studies demonstrate reduced activity of the R12Q variant compared to the wild type protein (PMID:25778938);; SCV005413782: PS3; SCV000469775: Kinetic analysis of the p.Arg12Gln variant by Sampaleanu et al. (2001) showed the Kcat was reduced by 18-fold and the Km was decreased by 2-fold, and Hu et al. (2015) reported that the p.Arg12Gln variant had a specific activity of 4.3% of wild type when expressed in HEK293T cells. PMID:24896178; PMID:31031587; SCV000631869: Experimental studies have shown that this missense change affects ASL function (PMID:11747432, 25778938).; SCV001193779: Functional assessments of this variant are available in the literature (PMID:11747432, 25778938, 31943503).; SCV002061272: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:25778938) - PS3_supporting."; SCV002503800: Impaired enzyme activity has been measured in patient red blood cells and in vitro functional assays expressing the variant (PMID:11747432, 20236848, 25778938).; SCV003922687: At least two publications report experimental evidence evaluating an impact on protein function and both found that the variant effect results in equal to or less than 10% of normal activity (e.g. Sampaleanu_2001, Hu_2015).; SCV005438712: Experimental studies have shown that this missense change affects ASL function Hu L et. al., 2015.; SCV003716104: In vitro functional studies demonstrate that this alteration leads to reduced enzyme activity when expressed in conjunction with a null allele or in homozygosity (Hu, 2015; Zielonka, 2020).; SCV004107595: "In functional studies, the activity of the argininosuccinate lyase enzyme containing the p.Arg12Gln substitution was decreased relative to wild-type (Sampaleanu et al. 2001. PubMed ID: 11747432; Hu et al. 2015. PubMed ID: 25778938)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 8.84
• Publications: 17 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238706: Functional expression studies demonstrate reduced activity of the R12Q variant compared to the wild type protein (PMID: 25778938);; SCV005413782: PS3; SCV000469775: Kinetic analysis of the p.Arg12Gln variant by Sampaleanu et al. (2001) showed the Kcat was reduced by 18-fold and the Km was decreased by 2-fold, and Hu et al. (2015) reported that the p.Arg12Gln variant had a specific activity of 4.3% of wild type when expressed in HEK293T cells. PMID:24896178; PMID:31031587; SCV000631869: Experimental studies have shown that this missense change affects ASL function (PMID: 11747432, 25778938).; SCV001193779: Functional assessments of this variant are available in the literature (PMID: 11747432, 25778938, 31943503).; SCV002061272: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 25778938) - PS3_supporting."; SCV002503800: Impaired enzyme activity has been measured in patient red blood cells and in vitro functional assays expressing the variant (PMID: 11747432, 20236848, 25778938).; SCV003922687: At least two publications report experimental evidence evaluating an impact on protein function and both found that the variant effect results in equal to or less than 10% of normal activity (e.g. Sampaleanu_2001, Hu_2015).; SCV005438712: Experimental studies have shown that this missense change affects ASL function Hu L et. al., 2015.; SCV003716104: In vitro functional studies demonstrate that this alteration leads to reduced enzyme activity when expressed in conjunction with a null allele or in homozygosity (Hu, 2015; Zielonka, 2020).; SCV004107595: "In functional studies, the activity of the argininosuccinate lyase enzyme containing the p.Arg12Gln substitution was decreased relative to wild-type (Sampaleanu et al. 2001. PubMed ID: 11747432; Hu et al. 2015. PubMed ID: 25778938)."
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66081824-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1518921.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.
• PP5: Variant 7-66081825-G-A is Pathogenic according to our data. Variant chr7-66081825-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 92360.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.35G>A	p.Arg12Gln	missense	Exon 3 of 17	NP_000039.2
	ASL	NM_001024943.2		c.35G>A	p.Arg12Gln	missense	Exon 2 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.35G>A	p.Arg12Gln	missense	Exon 2 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.35G>A	p.Arg12Gln	missense	Exon 3 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.35G>A	p.Arg12Gln	missense	Exon 2 of 16	ENSP00000378741.3	P04424-1
	ASL	ENST00000496336.1	TSL:1	n.276G>A		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00113 AC: 284 AN: 250818 AF XY: 0.00122

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00190 AC: 2779 AN: 1461506 Hom.: 1 Cov.: 31 AF XY: 0.00177 AC XY: 1286 AN XY: 727018

African (AFR) AF: 0.000418 AC: 14 AN: 33470

American (AMR) AF: 0.000403 AC: 18 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00232 AC: 2582 AN: 1111908

Other (OTH) AF: 0.00149 AC: 90 AN: 60378

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74448

African (AFR) AF: 0.000626 AC: 26 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15284

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00114 AC: 138

EpiCase AF: 0.00202

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	Argininosuccinate lyase deficiency (19)
6	-	-	not provided (6)
1	-	-	ASL-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.99
MPC		1.0
ClinPred		0.89	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.88
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145138923; hg19: chr7-65546812; COSMIC: COSV59188498;