rs796051925

Variant names:

• chr7-66087345-C-T
• rs796051925
• NM_000048.4:c.614C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000048.4(ASL):​c.614C>T​(p.Ala205Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,534 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A205T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.36
• 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: Myriad Women’s Health, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.97
• PP5: Variant 7-66087345-C-T is Pathogenic according to our data. Variant chr7-66087345-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203614.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.614C>T	p.Ala205Val	missense_variant	Exon 9 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.614C>T	p.Ala205Val	missense_variant	Exon 8 of 16		NP_001020114.1
ASL	NM_001024944.2	c.614C>T	p.Ala205Val	missense_variant	Exon 8 of 15		NP_001020115.1
ASL	NM_001024946.2	c.536C>T	p.Ala179Val	missense_variant	Exon 7 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.614C>T	p.Ala205Val	missense_variant	Exon 9 of 17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453534 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 723458

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.0000221 AC: 1 AN: 45178

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 205 of the ASL protein (p.Ala205Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829; 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: 203614). 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%. For these reasons, this variant has been classified as Pathogenic. -

Oct 09, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Aug 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ASL c.614C>T (p.Ala205Val) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244712 control chromosomes. c.614C>T has been reported in the literature in individuals affected with Argininosuccinic Aciduria (Balmer_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24166829). ClinVar contains an entry for this variant (Variation ID: 203614). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;M;.;M
PhyloP100		6.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		0.91	P;.;P;.;.
Vest4		0.96
MutPred		0.85		Loss of glycosylation at S201 (P = 0.1234);.;Loss of glycosylation at S201 (P = 0.1234);.;Loss of glycosylation at S201 (P = 0.1234);
MVP		0.99
MPC		0.58
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs796051925; hg19: chr7-65552332;