rs143793815

Variant names:

• chr7-66083120-C-T
• rs143793815
• NM_000048.4:c.392C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-66083120-C-T
• chr7-66083120-C-A
• chr7-66083120-C-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000048.4(ASL):​c.392C>T​(p.Thr131Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,686 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T131T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0460
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000048.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.7488 (below the threshold of 3.09). Trascript score misZ: 1.388 (below the threshold of 3.09). GenCC associations: The gene is linked to argininosuccinic aciduria.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013695866).
• BP6: Variant 7-66083120-C-T is Benign according to our data. Variant chr7-66083120-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 203625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000854 (130/152262) while in subpopulation SAS AF = 0.0126 (61/4824). AF 95% confidence interval is 0.0101. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

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.392C>T	p.Thr131Met	missense	Exon 6 of 17	NP_000039.2
	ASL	NM_001024943.2		c.392C>T	p.Thr131Met	missense	Exon 5 of 16	NP_001020114.1	A0A024RDL8
	ASL	NM_001024944.2		c.392C>T	p.Thr131Met	missense	Exon 5 of 15	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.392C>T	p.Thr131Met	missense	Exon 6 of 17	ENSP00000307188.9	P04424-1
	ASL	ENST00000395332.8	TSL:1	c.392C>T	p.Thr131Met	missense	Exon 5 of 16	ENSP00000378741.3	P04424-1
	ASL	ENST00000496336.1	TSL:1	n.773C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00235 AC: 588 AN: 250460 AF XY: 0.00305

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000744

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00132 AC: 1926 AN: 1461424 Hom.: 30 Cov.: 32 AF XY: 0.00178 AC XY: 1292 AN XY: 727004

African (AFR) AF: 0.000508 AC: 17 AN: 33474

American (AMR) AF: 0.000425 AC: 19 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0145 AC: 1251 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53074

Middle Eastern (MID) AF: 0.00877 AC: 50 AN: 5700

European-Non Finnish (NFE) AF: 0.000392 AC: 436 AN: 1111998

Other (OTH) AF: 0.00199 AC: 120 AN: 60376

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74430

African (AFR) AF: 0.000265 AC: 11 AN: 41556

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000867 Hom.: 0

Bravo AF: 0.000570

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00244 AC: 296

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Argininosuccinate lyase deficiency (5)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	5.6
DANN	Benign	0.85
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.046
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.54
Sift	Benign	0.081	T
Sift4G	Benign	0.11	T
Polyphen		0.18	B
Vest4		0.71
MVP		0.80
MPC		0.30
ClinPred		0.0089	T
GERP RS		-9.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.022
gMVP		0.60
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143793815; hg19: chr7-65548107;