7-66076320-C-G

Variant names:

• chr7-66076320-C-G
• rs1144895
• NM_000048.4:c.12+227C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000048.4(ASL):​c.12+227C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 152,050 control chromosomes in the GnomAD database, including 27,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.60 (27423 hom., cov: 33)
• Consequence: ASL NM_000048.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0910

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-66076320-C-G is Benign according to our data. Variant chr7-66076320-C-G is described in ClinVar as [Benign]. Clinvar id is 680525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.12+227C>G		intron_variant	Intron 2 of 16	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.12+227C>G		intron_variant	Intron 1 of 15		NP_001020114.1
ASL	NM_001024944.2	c.12+227C>G		intron_variant	Intron 1 of 14		NP_001020115.1
ASL	NM_001024946.2	c.12+227C>G		intron_variant	Intron 1 of 14		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.12+227C>G		intron_variant	Intron 2 of 16	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90417 AN: 151932 Hom.: 27391 Cov.: 33

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.574

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.595 AC: 90500 AN: 152050 Hom.: 27423 Cov.: 33 AF XY: 0.591 AC XY: 43921 AN XY: 74328

Gnomad4 AFR AF: 0.686

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.559

Gnomad4 NFE AF: 0.589

Gnomad4 OTH AF: 0.572

Alfa AF: 0.593 Hom.: 3365

Bravo AF: 0.598

Asia WGS AF: 0.390 AC: 1357 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.79

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: rs1144895; hg19: chr7-65541307; COSMIC: COSV59187992;