rs73374672

Positions:

• chr7-66081973-C-A
• chr7-66081973-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000304874.14(ASL):​c.183C>A​(p.Asp61Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D61D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASL ENST00000304874.14 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.597

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a helix (size 19) in uniprot entity ARLY_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000304874.14
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25075716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.183C>A	p.Asp61Glu	missense_variant	3/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.183C>A	p.Asp61Glu	missense_variant	2/16		NP_001020114.1
ASL	NM_001024944.2	c.183C>A	p.Asp61Glu	missense_variant	2/15		NP_001020115.1
ASL	NM_001024946.2	c.183C>A	p.Asp61Glu	missense_variant	2/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.183C>A	p.Asp61Glu	missense_variant	3/17	1	NM_000048.4	ENSP00000307188	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Uncertain	0.63	D;.;D;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	-0.045	N;N;N;N
MutationTaster	Benign	0.64	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.21	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.78	T;T;T;T
Sift4G	Benign	0.81	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.15
MutPred		0.49		Gain of ubiquitination at K57 (P = 0.0817);Gain of ubiquitination at K57 (P = 0.0817);Gain of ubiquitination at K57 (P = 0.0817);Gain of ubiquitination at K57 (P = 0.0817);
MVP		0.84
MPC		0.24
ClinPred		0.46	T
GERP RS		1.9
Varity_R		0.088
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs73374672; hg19: chr7-65546960;