rs746120802

Variant names:

• chr7-66092567-G-A
• rs746120802
• NM_000048.4:c.1154G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-66092567-G-A
• chr7-66092567-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000048.4(ASL):​c.1154G>A​(p.Arg385His) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,457,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R385C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 5.39
• 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: Orphanet, Myriad Women’s Health, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000249319 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66092566-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.7488 (below the threshold of 3.09). Trascript score misZ: 1.388 (below the threshold of 3.09). GenCC associations: The gene is linked to argininosuccinic aciduria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 7-66092567-G-A is Pathogenic according to our data. Variant chr7-66092567-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 552287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	NM_000048.4	MANE Select	c.1154G>A	p.Arg385His	missense	Exon 16 of 17	NP_000039.2
	ASL	NM_001024943.2		c.1154G>A	p.Arg385His	missense	Exon 15 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.1094G>A	p.Arg365His	missense	Exon 14 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.1154G>A	p.Arg385His	missense	Exon 16 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.1154G>A	p.Arg385His	missense	Exon 15 of 16	ENSP00000378741.3	P04424-1
	ENSG00000249319	ENST00000450043.2	TSL:5	c.467G>A	p.Arg156His	missense	Exon 7 of 12	ENSP00000396527.2	H7C0S8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247896 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1457082 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 725024

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5164

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000409 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	1	-	Argininosuccinate lyase deficiency (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.86
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs746120802; hg19: chr7-65557554;