rs143793815

Positions:

• chr7-66083120-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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:8
• Conservation: PhyloP100: 0.0460

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a helix (size 37) in uniprot entity ARLY_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000048.4
• 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 [Likely_benign]. Clinvar id is 203625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66083120-C-T is described in Lovd as [Pathogenic].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.392C>T	p.Thr131Met	missense_variant	6/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.392C>T	p.Thr131Met	missense_variant	5/16		NP_001020114.1
ASL	NM_001024944.2	c.392C>T	p.Thr131Met	missense_variant	5/15		NP_001020115.1
ASL	NM_001024946.2	c.392C>T	p.Thr131Met	missense_variant	5/15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.392C>T	p.Thr131Met	missense_variant	6/17	1	NM_000048.4	ENSP00000307188.9

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

GnomAD3 exomes AF: 0.00235 AC: 588 AN: 250460 Hom.: 6 AF XY: 0.00305 AC XY: 414 AN XY: 135632

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 SAS exome AF: 0.0147

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

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000392

Gnomad4 OTH exome AF: 0.00199

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

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000836 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

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Benign:5

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Thr131Met variant in ASL has been identified in the compound heterozygous state state in a Turkish individual with argininosuccinate lyase deficiency (PMID: 12384776), has been reported in at least 1 other individual not known to have disease (PMID: 25087612), and has been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive argininosuccinate lyase deficiency. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2022	Variant summary: ASL c.392C>T (p.Thr131Met) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250460 control chromosomes, predominantly at a frequency of 0.015 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ASL causing Argininosuccinic Aciduria phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

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;.;D;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.73	.;T;T;T;T
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.5	L;L;L;.;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.081	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.18	B;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs143793815; hg19: chr7-65548107;