7-66089173-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000048.4(ASL):c.916C>G(p.Arg306Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000668 in 149,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R306P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ASL
NM_000048.4 missense, splice_region

Scores

Splicing: ADA: 0.9071

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.78

Publications

2 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:

ENSG00000249319 (HGNC:):

ENSG00000249319 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 4 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

MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4 link	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	Exon 12 of 17	ENST00000304874.14	NP_000039.2	P04424-1A0A024RDL8
ASL	NM_001024943.2 link	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	Exon 11 of 16		NP_001020114.1	P04424-1A0A024RDL8
ASL	NM_001024944.2 link	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	Exon 11 of 15		NP_001020115.1	P04424-2
ASL	NM_001024946.2 link	c.838C>G	p.Arg280Gly	missense_variant, splice_region_variant	Exon 10 of 15		NP_001020117.1	A0A0S2Z316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14 link	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	Exon 12 of 17	1	NM_000048.4	ENSP00000307188.9		P04424-1
ENSG00000249319	ENST00000450043.2 link	c.229C>G	p.Arg77Gly	missense_variant, splice_region_variant	Exon 3 of 12	5		ENSP00000396527.2		H7C0S8

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149710

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1344422

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672660

African (AFR)

AF:

0.00

AC:

AN:

31126

American (AMR)

AF:

0.00

AC:

AN:

43690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24550

East Asian (EAS)

AF:

0.00

AC:

AN:

37054

South Asian (SAS)

AF:

0.00

AC:

AN:

83986

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1015816

Other (OTH)

AF:

0.00

AC:

AN:

55370

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149710

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73114

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41052

American (AMR)

AF:

0.00

AC:

AN:

15092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

4904

South Asian (SAS)

AF:

0.00

AC:

AN:

4586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67408

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.;D;D;.;.

Eigen

Benign

0.043

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

.;D;D;T;T;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.1

M;.;M;.;M;.

PhyloP100

1.8

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.9

D;D;D;D;D;.

REVEL

Pathogenic

0.74

Sift

Benign

0.19

T;T;T;D;D;.

Sift4G

Benign

0.28

T;T;T;D;D;T

Polyphen

0.33

B;.;B;.;.;.

Vest4

0.63

MutPred

0.50

Loss of MoRF binding (P = 0.0031);.;Loss of MoRF binding (P = 0.0031);.;Loss of MoRF binding (P = 0.0031);.;

MVP

0.95

MPC

0.45

ClinPred

0.98

GERP RS

4.8

PromoterAI

-0.083

Neutral

(source)

Varity_R

0.71

gMVP

0.88

Mutation Taster

=10/90

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.18

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over