7-66086788-T-TGCGGAA

Variant names:

• chr7-66086788-T-TGCGGAA
• rs869312989
• NM_000048.4:c.575_580dupAGCGGA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The NM_000048.4(ASL):​c.575_580dupAGCGGA​(p.Lys192_Arg193dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I194I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASL NM_000048.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0800
• Publications: 0 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: Myriad Women’s Health, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000048.4.
• PP5: Variant 7-66086788-T-TGCGGAA is Pathogenic according to our data. Variant chr7-66086788-T-TGCGGAA is described in ClinVar as Pathogenic. ClinVar VariationId is 224974.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	NM_000048.4	MANE Select	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	Exon 8 of 17	NP_000039.2
	ASL	NM_001024943.2		c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	Exon 7 of 16	NP_001020114.1
	ASL	NM_001024944.2		c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	Exon 7 of 15	NP_001020115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	ENST00000304874.14	TSL:1 MANE Select	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	Exon 8 of 17	ENSP00000307188.9
	ASL	ENST00000395332.8	TSL:1	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	Exon 7 of 16	ENSP00000378741.3
	ASL	ENST00000395331.4	TSL:5	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	Exon 7 of 15	ENSP00000378740.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:1

SNPedia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.080
Mutation Taster		=54/46	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869312989; hg19: chr7-65551775;