rs117035302

Variant names:

• chr7-66087805-A-T
• rs117035302
• NM_000048.4:c.718+14A>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000048.4(ASL):​c.718+14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,052 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (62 hom., cov: 32)
  • Exomes 𝑓: 0.011 (446 hom.)
• Consequence: ASL NM_000048.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.329

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]

ENSG00000249319 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-66087805-A-T is Benign according to our data. Variant chr7-66087805-A-T is described in ClinVar as [Benign]. Clinvar id is 254742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66087805-A-T is described in Lovd as [Benign]. Variant chr7-66087805-A-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.718+14A>T		intron_variant	Intron 10 of 16	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.718+14A>T		intron_variant	Intron 9 of 15		NP_001020114.1
ASL	NM_001024944.2	c.718+14A>T		intron_variant	Intron 9 of 14		NP_001020115.1
ASL	NM_001024946.2	c.640+14A>T		intron_variant	Intron 8 of 14		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.718+14A>T		intron_variant	Intron 10 of 16	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.31+14A>T		intron_variant	Intron 1 of 11	5		ENSP00000396527.2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2515 AN: 152132 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0926

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0226 AC: 5676 AN: 251186 Hom.: 142 AF XY: 0.0205 AC XY: 2785 AN XY: 135834

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0868

Gnomad SAS exome AF: 0.00523

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.00612

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0108 AC: 15726 AN: 1461802 Hom.: 446 Cov.: 32 AF XY: 0.0105 AC XY: 7614 AN XY: 727198

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.0381

Gnomad4 ASJ exome AF: 0.00608

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.00583

Gnomad4 FIN exome AF: 0.0693

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0166 AC: 2527 AN: 152250 Hom.: 62 Cov.: 32 AF XY: 0.0196 AC XY: 1458 AN XY: 74432

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.0247

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0926

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0755

Gnomad4 NFE AF: 0.00566

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.0105 Hom.: 1

Bravo AF: 0.0132

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 17, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Argininosuccinate lyase deficiency Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs117035302; hg19: chr7-65552792; COSMIC: COSV59189172; COSMIC: COSV59189172;