Genetic Variant NM_000048.4:c.332G>A (chr7-66082920-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM5PP2PP3_StrongPP5

The NM_000048.4(ASL):c.332G>A(p.Arg111Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R111W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 1 hom. )

Consequence

ASL
NM_000048.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2

Conservation

PhyloP100: 8.78

Publications

1 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: Orphanet, Myriad Women’s Health, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ASL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_000048.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-66082919-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1489478.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, 0.979

PP5

Variant 7-66082920-G-A is Pathogenic according to our data. Variant chr7-66082920-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288770.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASL	NM_000048.4	MANE Select	c.332G>A	p.Arg111Gln	missense	Exon 5 of 17	NP_000039.2
ASL	NM_001024943.2		c.332G>A	p.Arg111Gln	missense	Exon 4 of 16	NP_001020114.1	A0A024RDL8
ASL	NM_001024944.2		c.332G>A	p.Arg111Gln	missense	Exon 4 of 15	NP_001020115.1	P04424-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASL	ENST00000304874.14	TSL:1 MANE Select	c.332G>A	p.Arg111Gln	missense	Exon 5 of 17	ENSP00000307188.9	P04424-1
ASL	ENST00000395332.8	TSL:1	c.332G>A	p.Arg111Gln	missense	Exon 4 of 16	ENSP00000378741.3	P04424-1
ASL	ENST00000496336.1	TSL:1	n.573G>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000600

AC:

AN:

250184

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111998

Other (OTH)

AF:

0.0000166

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74404

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41530

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000577

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Argininosuccinate lyase deficiency (8)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.5

PhyloP100

8.8

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MutPred

0.86

Loss of catalytic residue at S112 (P = 0.0064)

MVP

0.99

MPC

1.0

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.97

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over