rs142448820

Positions:

• chr7-66082897-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000048.4(ASL):​c.309G>A​(p.Thr103Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ASL NM_000048.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.03

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-66082897-G-A is Benign according to our data. Variant chr7-66082897-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 389364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66082897-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00124 (189/152148) while in subpopulation AFR AF= 0.00383 (159/41522). AF 95% confidence interval is 0.00334. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.309G>A	p.Thr103Thr	synonymous_variant	5/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.309G>A	p.Thr103Thr	synonymous_variant	4/16		NP_001020114.1
ASL	NM_001024944.2	c.309G>A	p.Thr103Thr	synonymous_variant	4/15		NP_001020115.1
ASL	NM_001024946.2	c.309G>A	p.Thr103Thr	synonymous_variant	4/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.309G>A	p.Thr103Thr	synonymous_variant	5/17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000447 AC: 112 AN: 250524 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135686

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000195 AC: 285 AN: 1461570 Hom.: 0 Cov.: 31 AF XY: 0.000213 AC XY: 155 AN XY: 727066

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74390

Gnomad4 AFR AF: 0.00383

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000671 Hom.: 0

Bravo AF: 0.00141

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	ASL: BP4, BP7 -

Argininosuccinate lyase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.20
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)		0.0		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: rs142448820; hg19: chr7-65547884;