7-66089173-C-G

Variant names:

• chr7-66089173-C-G
• rs868834862
• NM_000048.4:c.916C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

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

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

ENSG00000249319 (HGNC:):

ACMG classification

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, 5 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	NM_000048.4	MANE Select	c.916C>G	p.Arg306Gly	missense splice_region	Exon 12 of 17	NP_000039.2
	ASL	NM_001024943.2		c.916C>G	p.Arg306Gly	missense splice_region	Exon 11 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.916C>G	p.Arg306Gly	missense splice_region	Exon 11 of 15	NP_001020115.1	P04424-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	ENST00000304874.14	TSL:1 MANE Select	c.916C>G	p.Arg306Gly	missense splice_region	Exon 12 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.916C>G	p.Arg306Gly	missense splice_region	Exon 11 of 16	ENSP00000378741.3	P04424-1
	ENSG00000249319	ENST00000450043.2	TSL:5	c.229C>G	p.Arg77Gly	missense splice_region	Exon 3 of 12	ENSP00000396527.2	H7C0S8

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149710 Hom.: 0 Cov.: 32

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: 0 AN: 1344422 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 672660

African (AFR) AF: 0.00 AC: 0 AN: 31126

American (AMR) AF: 0.00 AC: 0 AN: 43690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24550

East Asian (EAS) AF: 0.00 AC: 0 AN: 37054

South Asian (SAS) AF: 0.00 AC: 0 AN: 83986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1015816

Other (OTH) AF: 0.00 AC: 0 AN: 55370

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149710 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73114

African (AFR) AF: 0.0000244 AC: 1 AN: 41052

American (AMR) AF: 0.00 AC: 0 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 4904

South Asian (SAS) AF: 0.00 AC: 0 AN: 4586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67408

Other (OTH) AF: 0.00 AC: 0 AN: 2060

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	0.043
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.74
Sift	Benign	0.19	T
Sift4G	Benign	0.28	T
Polyphen		0.33	B
Vest4		0.63
MutPred		0.50		Loss of MoRF binding (P = 0.0031)
MVP		0.95
MPC		0.45
ClinPred		0.98	D
GERP RS		4.8
PromoterAI		-0.083	Neutral
Varity_R		0.71
gMVP		0.88
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs868834862; hg19: chr7-65554160;