NM_000048.4:c.718+14A>T

Variant names:

• chr7-66087805-A-T
• rs117035302
• NM_000048.4:c.718+14A>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.718+14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,052 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (62 hom., cov: 32)
  • Exomes 𝑓: 0.011 (446 hom.)
• Consequence: ASL NM_000048.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.329
• Publications: 2 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: Orphanet, Myriad Women’s Health, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000249319 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-66087805-A-T is Benign according to our data. Variant chr7-66087805-A-T is described in ClinVar as Benign. ClinVar VariationId is 254742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000048.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	NM_000048.4	MANE Select	c.718+14A>T		intron	N/A	NP_000039.2
	ASL	NM_001024943.2		c.718+14A>T		intron	N/A	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.718+14A>T		intron	N/A	NP_001020115.1	P04424-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	ENST00000304874.14	TSL:1 MANE Select	c.718+14A>T		intron	N/A	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.718+14A>T		intron	N/A	ENSP00000378741.3	P04424-1
	ENSG00000249319	ENST00000450043.2	TSL:5	c.31+14A>T		intron	N/A	ENSP00000396527.2	H7C0S8

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2515 AN: 152132 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0926

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0226 AC: 5676 AN: 251186 AF XY: 0.0205

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0868

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.00612

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0108 AC: 15726 AN: 1461802 Hom.: 446 Cov.: 32 AF XY: 0.0105 AC XY: 7614 AN XY: 727198

African (AFR) AF: 0.0106 AC: 354 AN: 33480

American (AMR) AF: 0.0381 AC: 1702 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 159 AN: 26134

East Asian (EAS) AF: 0.104 AC: 4146 AN: 39694

South Asian (SAS) AF: 0.00583 AC: 503 AN: 86258

European-Finnish (FIN) AF: 0.0693 AC: 3698 AN: 53382

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.00368 AC: 4096 AN: 1111974

Other (OTH) AF: 0.0169 AC: 1018 AN: 60392

GnomAD4 genome AF: 0.0166 AC: 2527 AN: 152250 Hom.: 62 Cov.: 32 AF XY: 0.0196 AC XY: 1458 AN XY: 74432

African (AFR) AF: 0.00883 AC: 367 AN: 41550

American (AMR) AF: 0.0247 AC: 378 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.0926 AC: 479 AN: 5174

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4828

European-Finnish (FIN) AF: 0.0755 AC: 801 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00566 AC: 385 AN: 68022

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0105 Hom.: 1

Bravo AF: 0.0132

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Argininosuccinate lyase deficiency (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.70
PhyloP100		-0.33
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs117035302; hg19: chr7-65552792; COSMIC: COSV59189172; COSMIC: COSV59189172;