rs115468878

Positions:

• chr7-66086795-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000048.4(ASL):​c.576G>A​(p.Lys192Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,588,272 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (8 hom.)
• Consequence: ASL NM_000048.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00100

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 7-66086795-G-A is Benign according to our data. Variant chr7-66086795-G-A is described in ClinVar as [Benign]. Clinvar id is 92363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.001 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00652 (993/152268) while in subpopulation AFR AF= 0.0224 (931/41564). AF 95% confidence interval is 0.0212. There are 14 homozygotes in gnomad4. There are 473 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.576G>A	p.Lys192Lys	synonymous_variant	8/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.576G>A	p.Lys192Lys	synonymous_variant	7/16		NP_001020114.1
ASL	NM_001024944.2	c.576G>A	p.Lys192Lys	synonymous_variant	7/15		NP_001020115.1
ASL	NM_001024946.2	c.524+133G>A		intron_variant			NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.576G>A	p.Lys192Lys	synonymous_variant	8/17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 988 AN: 152150 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00147 AC: 297 AN: 202682 Hom.: 1 AF XY: 0.000996 AC XY: 109 AN XY: 109396

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.000693

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000227

Gnomad OTH exome AF: 0.000576

GnomAD4 exome AF: 0.000596 AC: 856 AN: 1436004 Hom.: 8 Cov.: 32 AF XY: 0.000525 AC XY: 374 AN XY: 712220

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.000848

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152268 Hom.: 14 Cov.: 33 AF XY: 0.00635 AC XY: 473 AN XY: 74454

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00765

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Argininosuccinate lyase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 22, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.0
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs115468878; hg19: chr7-65551782;