7-66092862-G-T

Variant names:

• chr7-66092862-G-T
• NM_000048.4:c.1345G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000048.4(ASL):​c.1345G>T​(p.Asp449Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,266 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52

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 2 ACMG points.

• 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.1345G>T	p.Asp449Tyr	missense_variant	Exon 17 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.1345G>T	p.Asp449Tyr	missense_variant	Exon 16 of 16		NP_001020114.1
ASL	NM_001024944.2	c.1285G>T	p.Asp429Tyr	missense_variant	Exon 15 of 15		NP_001020115.1
ASL	NM_001024946.2	c.1267G>T	p.Asp423Tyr	missense_variant	Exon 15 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.1345G>T	p.Asp449Tyr	missense_variant	Exon 17 of 17	1	NM_000048.4	ENSP00000307188.9
ENSG00000249319	ENST00000450043.2	c.563+199G>T		intron_variant	Intron 7 of 11	5		ENSP00000396527.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460266 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726506

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Uncertain	0.47	T;.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.7	L;.;L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.30	N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.15	T;T;T;T
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		0.91	P;.;P;.
Vest4		0.27
MutPred		0.38		Gain of MoRF binding (P = 0.0673);.;Gain of MoRF binding (P = 0.0673);.;
MVP		0.94
MPC		0.52
ClinPred		0.23	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-65557849;