7-66076086-C-T

Variant names:

• chr7-66076086-C-T
• rs149918397
• NM_000048.4:c.5C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000048.4(ASL):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity ARLY_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.5C>T	p.Ala2Val	missense_variant	Exon 2 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 16		NP_001020114.1
ASL	NM_001024944.2	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 15		NP_001020115.1
ASL	NM_001024946.2	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.5C>T	p.Ala2Val	missense_variant	Exon 2 of 17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000456 AC: 1 AN: 219432 Hom.: 0 AF XY: 0.00000836 AC XY: 1 AN XY: 119586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000592

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447412 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718586

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 Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;T;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	.;T;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.4	L;L;L;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.027	D;D;D;T;D
Sift4G	Uncertain	0.038	D;D;D;T;D
Polyphen		0.92	P;.;P;.;.
Vest4		0.58
MutPred		0.21		Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);
MVP		0.95
MPC		0.50
ClinPred		0.87	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs149918397; hg19: chr7-65541073;