Genetic Variant NM_000048.4:c.2T>C (chr7-66076083-T-C) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000048.4(ASL):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,946 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 (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ASL
NM_000048.4 start_lost

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.96

Publications

0 publications found

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 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

ASL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 21 codons. Genomic position: 66081851. Lost 0.044 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-66076083-T-C is Pathogenic according to our data. Variant chr7-66076083-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4061682.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4 link	c.2T>C	p.Met1?	start_lost	Exon 2 of 17	ENST00000304874.14	NP_000039.2	P04424-1A0A024RDL8
ASL	NM_001024943.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 16		NP_001020114.1	P04424-1A0A024RDL8
ASL	NM_001024944.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 15		NP_001020115.1	P04424-2
ASL	NM_001024946.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 15		NP_001020117.1	A0A0S2Z316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14 link	c.2T>C	p.Met1?	start_lost	Exon 2 of 17	1	NM_000048.4	ENSP00000307188.9		P04424-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33212

American (AMR)

AF:

0.00

AC:

AN:

43110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25806

East Asian (EAS)

AF:

0.00

AC:

AN:

39070

South Asian (SAS)

AF:

0.00

AC:

AN:

83632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106056

Other (OTH)

AF:

0.00

AC:

AN:

59854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Argininosuccinate lyase deficiency

Pathogenic:1

Feb 04, 2025

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;.;D;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

.;D;D;D;D

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

PhyloP100

2.0

PROVEAN

Uncertain

-2.7

D;D;D;N;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;D;T;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

0.97

D;.;D;.;.

Vest4

0.89

MutPred

0.98

Gain of catalytic residue at M1 (P = 0.0327);Gain of catalytic residue at M1 (P = 0.0327);Gain of catalytic residue at M1 (P = 0.0327);Gain of catalytic residue at M1 (P = 0.0327);Gain of catalytic residue at M1 (P = 0.0327);

MVP

0.98

ClinPred

0.98

GERP RS

3.9

PromoterAI

-0.30

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.69

Mutation Taster

=23/177

disease causing

(source)

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

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NM_000048.4:c.2T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over