7-66086834-C-T

Variant names:

• chr7-66086834-C-T
• rs12536292
• NM_000048.4:c.602+13C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000048.4(ASL):​c.602+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,563,968 control chromosomes in the GnomAD database, including 2,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (191 hom., cov: 32)
  • Exomes 𝑓: 0.048 (1877 hom.)
• Consequence: ASL NM_000048.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.21
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-66086834-C-T is Benign according to our data. Variant chr7-66086834-C-T is described in ClinVar as Benign. ClinVar VariationId is 92364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

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.602+13C>T		intron	N/A	NP_000039.2
	ASL	NM_001024943.2		c.602+13C>T		intron	N/A	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.602+13C>T		intron	N/A	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.602+13C>T		intron	N/A	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.602+13C>T		intron	N/A	ENSP00000378741.3	P04424-1
	ASL	ENST00000906815.1		c.695+13C>T		intron	N/A	ENSP00000576874.1

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 6676 AN: 152126 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.0847

Gnomad SAS AF: 0.0394

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0513 AC: 8781 AN: 171318 AF XY: 0.0515

Gnomad AFR exome AF: 0.0307

Gnomad AMR exome AF: 0.0583

Gnomad ASJ exome AF: 0.0433

Gnomad EAS exome AF: 0.0748

Gnomad FIN exome AF: 0.0838

Gnomad NFE exome AF: 0.0436

Gnomad OTH exome AF: 0.0553

GnomAD4 exome AF: 0.0476 AC: 67238 AN: 1411724 Hom.: 1877 Cov.: 32 AF XY: 0.0473 AC XY: 33015 AN XY: 697980

African (AFR) AF: 0.0321 AC: 1041 AN: 32408

American (AMR) AF: 0.0550 AC: 2029 AN: 36898

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 1125 AN: 25274

East Asian (EAS) AF: 0.111 AC: 4096 AN: 37054

South Asian (SAS) AF: 0.0429 AC: 3467 AN: 80768

European-Finnish (FIN) AF: 0.0805 AC: 3874 AN: 48144

Middle Eastern (MID) AF: 0.0926 AC: 528 AN: 5704

European-Non Finnish (NFE) AF: 0.0443 AC: 48118 AN: 1086852

Other (OTH) AF: 0.0505 AC: 2960 AN: 58622

GnomAD4 genome AF: 0.0438 AC: 6674 AN: 152244 Hom.: 191 Cov.: 32 AF XY: 0.0463 AC XY: 3446 AN XY: 74440

African (AFR) AF: 0.0324 AC: 1346 AN: 41568

American (AMR) AF: 0.0487 AC: 745 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3468

East Asian (EAS) AF: 0.0848 AC: 438 AN: 5168

South Asian (SAS) AF: 0.0388 AC: 187 AN: 4820

European-Finnish (FIN) AF: 0.0760 AC: 806 AN: 10610

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0422 AC: 2871 AN: 68006

Other (OTH) AF: 0.0469 AC: 99 AN: 2112

Alfa AF: 0.0274 Hom.: 17

Bravo AF: 0.0425

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.95
DANN	Benign	0.81
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs12536292; hg19: chr7-65551821; COSMIC: COSV59188566; COSMIC: COSV59188566;