7-66092577-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.46

Publications

6 publications found

Variant links:

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

ASL links:

ENSG00000249319 (HGNC:):

ENSG00000249319 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ASL	NM_000048.4 link	c.1164C>T	p.His388His	synonymous_variant	Exon 16 of 17	ENST00000304874.14	NP_000039.2	P04424-1A0A024RDL8
ASL	NM_001024943.2 link	c.1164C>T	p.His388His	synonymous_variant	Exon 15 of 16		NP_001020114.1	P04424-1A0A024RDL8
ASL	NM_001024944.2 link	c.1104C>T	p.His368His	synonymous_variant	Exon 14 of 15		NP_001020115.1	P04424-2
ASL	NM_001024946.2 link	c.1086C>T	p.His362His	synonymous_variant	Exon 14 of 15		NP_001020117.1	A0A0S2Z316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14 link	c.1164C>T	p.His388His	synonymous_variant	Exon 16 of 17	1	NM_000048.4	ENSP00000307188.9		P04424-1
ENSG00000249319	ENST00000450043.2 link	c.477C>T	p.His159His	synonymous_variant	Exon 7 of 12	5		ENSP00000396527.2		H7C0S8

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2264

AN:

152116

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0218

AC:

5427

AN:

248716

AF XY:

0.0199

show subpopulations

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 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.:

AF XY:

0.0102

AC XY:

7406

AN XY:

725764

show subpopulations

African (AFR)

AF:

0.00439

AC:

147

AN:

33468

American (AMR)

AF:

0.0377

AC:

1684

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00608

AC:

159

AN:

26136

East Asian (EAS)

AF:

0.105

AC:

4149

AN:

39698

South Asian (SAS)

AF:

0.00583

AC:

503

AN:

86232

European-Finnish (FIN)

AF:

0.0688

AC:

3486

AN:

50660

Middle Eastern (MID)

AF:

0.00899

AC:

AN:

5448

European-Non Finnish (NFE)

AF:

0.00368

AC:

4093

AN:

1111960

Other (OTH)

AF:

0.0164

AC:

992

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

905

1809

2714

3618

4523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0149

AC:

2274

AN:

152230

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1329

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00330

AC:

137

AN:

41568

American (AMR)

AF:

0.0242

AC:

369

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.0914

AC:

471

AN:

5154

South Asian (SAS)

AF:

0.00830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0752

AC:

798

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00566

AC:

385

AN:

68024

Other (OTH)

AF:

0.0237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

102

203

305

406

508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00797

Hom.:

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

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 05, 2014

Eurofins Ntd Llc (ga)

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

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Argininosuccinate lyase deficiency

Benign:4

Nov 26, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

2.8

(source)

DANN

Benign

0.70

PhyloP100

-3.5

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over