chr7-66089173-C-G

Position:

• chr7-66089173-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 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.

• 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

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]

ENSG00000249319 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 23) in uniprot entity ARLY_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	12/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	11/16		NP_001020114.1
ASL	NM_001024944.2	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	11/15		NP_001020115.1
ASL	NM_001024946.2	c.838C>G	p.Arg280Gly	missense_variant, splice_region_variant	10/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.916C>G	p.Arg306Gly	missense_variant, splice_region_variant	12/17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.229C>G	p.Arg77Gly	missense_variant, splice_region_variant	3/12	5		ENSP00000396527.2

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

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
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	D
LIST_S2	Pathogenic	0.99	.;D;D;T;T;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M;.;M;.;M;.
PrimateAI	Uncertain	0.78	T
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	D
GERP RS		4.8
Varity_R		0.71
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs868834862; hg19: chr7-65554160;