7-66076198-C-T

Variant names:

• chr7-66076198-C-T
• rs1183245
• NM_000048.4:c.12+105C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000048.4(ASL):​c.12+105C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,451,750 control chromosomes in the GnomAD database, including 244,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27724 hom., cov: 33)
  • Exomes 𝑓: 0.57 (216893 hom.)
• Consequence: ASL NM_000048.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.303
• Publications: 11 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: Myriad Women’s Health, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-66076198-C-T is Benign according to our data. Variant chr7-66076198-C-T is described in ClinVar as [Benign]. Clinvar id is 1177030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.12+105C>T		intron_variant	Intron 2 of 16	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.12+105C>T		intron_variant	Intron 1 of 15		NP_001020114.1
ASL	NM_001024944.2	c.12+105C>T		intron_variant	Intron 1 of 14		NP_001020115.1
ASL	NM_001024946.2	c.12+105C>T		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+105C>T		intron_variant	Intron 2 of 16	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90845 AN: 151928 Hom.: 27686 Cov.: 33

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.575

GnomAD4 exome AF: 0.573 AC: 745152 AN: 1299706 Hom.: 216893 AF XY: 0.569 AC XY: 366299 AN XY: 643758

African (AFR) AF: 0.702 AC: 20485 AN: 29182

American (AMR) AF: 0.532 AC: 17444 AN: 32766

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 13597 AN: 23828

East Asian (EAS) AF: 0.323 AC: 11284 AN: 34884

South Asian (SAS) AF: 0.480 AC: 36662 AN: 76352

European-Finnish (FIN) AF: 0.555 AC: 26197 AN: 47206

Middle Eastern (MID) AF: 0.481 AC: 2611 AN: 5426

European-Non Finnish (NFE) AF: 0.589 AC: 586507 AN: 995780

Other (OTH) AF: 0.559 AC: 30365 AN: 54282

GnomAD4 genome AF: 0.598 AC: 90939 AN: 152044 Hom.: 27724 Cov.: 33 AF XY: 0.594 AC XY: 44127 AN XY: 74330

African (AFR) AF: 0.697 AC: 28916 AN: 41494

American (AMR) AF: 0.561 AC: 8564 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1981 AN: 3468

East Asian (EAS) AF: 0.307 AC: 1585 AN: 5162

South Asian (SAS) AF: 0.456 AC: 2196 AN: 4820

European-Finnish (FIN) AF: 0.560 AC: 5926 AN: 10588

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.589 AC: 40002 AN: 67936

Other (OTH) AF: 0.574 AC: 1209 AN: 2108

Alfa AF: 0.594 Hom.: 3378

Bravo AF: 0.601

Asia WGS AF: 0.395 AC: 1372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Argininosuccinate lyase deficiency Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.42
PhyloP100		-0.30
PromoterAI		0.042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1183245; hg19: chr7-65541185; COSMIC: COSV59189044; COSMIC: COSV59189044;