NM_000048.4:c.556C>A

Variant names:

• chr7-66086775-C-A
• rs111407265
• NM_000048.4:c.556C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000048.4(ASL):​c.556C>A​(p.Arg186Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000888 in 1,599,348 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: ASL NM_000048.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.23
• Publications: 9 publications found

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: Orphanet, Myriad Women’s Health, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 7-66086775-C-A is Benign according to our data. Variant chr7-66086775-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00422 (643/152260) while in subpopulation AFR AF = 0.0134 (558/41558). AF 95% confidence interval is 0.0125. There are 7 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000048.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	NM_000048.4	MANE Select	c.556C>A	p.Arg186Arg	synonymous	Exon 8 of 17	NP_000039.2
	ASL	NM_001024943.2		c.556C>A	p.Arg186Arg	synonymous	Exon 7 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.556C>A	p.Arg186Arg	synonymous	Exon 7 of 15	NP_001020115.1	P04424-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	ENST00000304874.14	TSL:1 MANE Select	c.556C>A	p.Arg186Arg	synonymous	Exon 8 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.556C>A	p.Arg186Arg	synonymous	Exon 7 of 16	ENSP00000378741.3	P04424-1
	ASL	ENST00000906815.1		c.649C>A	p.Arg217Arg	synonymous	Exon 9 of 18	ENSP00000576874.1

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 642 AN: 152142 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00110 AC: 244 AN: 221462 AF XY: 0.000832

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000538 AC: 778 AN: 1447088 Hom.: 7 Cov.: 32 AF XY: 0.000480 AC XY: 345 AN XY: 718840

African (AFR) AF: 0.0126 AC: 420 AN: 33276

American (AMR) AF: 0.00197 AC: 83 AN: 42056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 39096

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51220

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5752

European-Non Finnish (NFE) AF: 0.000139 AC: 154 AN: 1105554

Other (OTH) AF: 0.00174 AC: 104 AN: 59816

GnomAD4 genome AF: 0.00422 AC: 643 AN: 152260 Hom.: 7 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74452

African (AFR) AF: 0.0134 AC: 558 AN: 41558

American (AMR) AF: 0.00379 AC: 58 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00210 Hom.: 1

Bravo AF: 0.00466

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Argininosuccinate lyase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.1
DANN	Benign	0.82
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs111407265; hg19: chr7-65551762;