chr7-66089173-C-T

Variant names:

• chr7-66089173-C-T
• rs868834862
• NM_000048.4:c.916C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000048.4(ASL):​c.916C>T​(p.Arg306Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R306P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASL NM_000048.4 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.78
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, Myriad Women’s Health

ENSG00000249319 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.916C>T	p.Arg306Trp	missense splice_region	Exon 12 of 17	NP_000039.2
	ASL	NM_001024943.2		c.916C>T	p.Arg306Trp	missense splice_region	Exon 11 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.916C>T	p.Arg306Trp	missense splice_region	Exon 11 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.916C>T	p.Arg306Trp	missense splice_region	Exon 12 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.916C>T	p.Arg306Trp	missense splice_region	Exon 11 of 16	ENSP00000378741.3	P04424-1
	ENSG00000249319	ENST00000450043.2	TSL:5	c.229C>T	p.Arg77Trp	missense splice_region	Exon 3 of 12	ENSP00000396527.2	H7C0S8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Argininosuccinate lyase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Benign	0.015
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.082	T
Polyphen		0.12	B
Vest4		0.92
MutPred		0.52		Loss of methylation at R306 (P = 0.0099)
MVP		0.95
MPC		0.28
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.89
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
Splicevardb		3.0
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.90		Position offset: -2
DS_DL_spliceai		0.41		Position offset: 2

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

Other links and lift over

dbSNP: rs868834862; hg19: chr7-65554160; COSMIC: COSV59189662; COSMIC: COSV59189662;