7-66092577-C-T

Position:

• chr7-66092577-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000048.4(ASL):​c.1164C>T​(p.His388His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,610,882 control chromosomes in the GnomAD database, including 499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (60 hom., cov: 32)
  • Exomes 𝑓: 0.010 (439 hom.)
• Consequence: ASL NM_000048.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.46

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-66092577-C-T is Benign according to our data. Variant chr7-66092577-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66092577-C-T is described in Lovd as [Benign]. Variant chr7-66092577-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.1164C>T	p.His388His	synonymous_variant	16/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.1164C>T	p.His388His	synonymous_variant	15/16		NP_001020114.1
ASL	NM_001024944.2	c.1104C>T	p.His368His	synonymous_variant	14/15		NP_001020115.1
ASL	NM_001024946.2	c.1086C>T	p.His362His	synonymous_variant	14/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.1164C>T	p.His388His	synonymous_variant	16/17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.477C>T	p.His159His	synonymous_variant	7/12	5		ENSP00000396527.2

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2264 AN: 152116 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0218 AC: 5427 AN: 248716 Hom.: 141 AF XY: 0.0199 AC XY: 2678 AN XY: 134864

Gnomad AFR exome AF: 0.00292

Gnomad AMR exome AF: 0.0399

Gnomad ASJ exome AF: 0.00587

Gnomad EAS exome AF: 0.0872

Gnomad SAS exome AF: 0.00523

Gnomad FIN exome AF: 0.0674

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0105 AC: 15262 AN: 1458652 Hom.: 439 Cov.: 32 AF XY: 0.0102 AC XY: 7406 AN XY: 725764

Gnomad4 AFR exome AF: 0.00439

Gnomad4 AMR exome AF: 0.0377

Gnomad4 ASJ exome AF: 0.00608

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.00583

Gnomad4 FIN exome AF: 0.0688

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.0164

GnomAD4 genome AF: 0.0149 AC: 2274 AN: 152230 Hom.: 60 Cov.: 32 AF XY: 0.0179 AC XY: 1329 AN XY: 74404

Gnomad4 AFR AF: 0.00330

Gnomad4 AMR AF: 0.0242

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0914

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0752

Gnomad4 NFE AF: 0.00566

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.00594 Hom.: 2

Bravo AF: 0.0112

Asia WGS AF: 0.0720 AC: 249 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2014	- -

Argininosuccinate lyase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.8
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs75300185; hg19: chr7-65557564;