Variant 7-66089678-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000048.4(ASL):c.1045G>C(p.Val349Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V349I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASL
NM_000048.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.11

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ASL	NM_000048.4 linkuse as main transcript	c.1045G>C	p.Val349Leu	missense_variant	14/17	ENST00000304874.14
ASL	NM_001024943.2 linkuse as main transcript	c.1045G>C	p.Val349Leu	missense_variant	13/16
ASL	NM_001024944.2 linkuse as main transcript	c.985G>C	p.Val329Leu	missense_variant	12/15
ASL	NM_001024946.2 linkuse as main transcript	c.967G>C	p.Val323Leu	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASL	ENST00000304874.14 linkuse as main transcript	c.1045G>C	p.Val349Leu	missense_variant	14/17	1	NM_000048.4	P1	P04424-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250538

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135672

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;D;.;.

Eigen

Benign

-0.091

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

1.7

L;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

D;D;D;D;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.0030

D;D;D;D;.

Sift4G

Benign

0.095

T;T;T;T;T

Polyphen

0.054

B;.;B;.;.

Vest4

0.63

MutPred

0.53

Loss of catalytic residue at V349 (P = 0.1002);.;Loss of catalytic residue at V349 (P = 0.1002);.;.;

MVP

0.85

MPC

0.28

ClinPred

0.87

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over