9-130458549-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_054012.4(ASS1):c.323G>T(p.Arg108Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,360 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (19 hom.)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:9
• Conservation: PhyloP100: 0.908

Genes affected

ASS1 (HGNC:758): (argininosuccinate synthase 1) The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00918442).
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4	c.323G>T	p.Arg108Leu	missense_variant	4/15	ENST00000352480.10
ASS1	NM_000050.4	c.323G>T	p.Arg108Leu	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.323G>T	p.Arg108Leu	missense_variant	4/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 847 AN: 152228 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00295 AC: 736 AN: 249624 Hom.: 7 AF XY: 0.00246 AC XY: 333 AN XY: 135330

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00559

Gnomad ASJ exome AF: 0.00680

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00170 AC: 2480 AN: 1461014 Hom.: 19 Cov.: 32 AF XY: 0.00169 AC XY: 1226 AN XY: 726802

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152346 Hom.: 4 Cov.: 33 AF XY: 0.00534 AC XY: 398 AN XY: 74506

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00628

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00299 AC: 363

EpiCase AF: 0.00164

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Citrullinemia type I Pathogenic:1 Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2018	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: ASS1 c.323G>T (p.Arg108Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0038 in 394424 control chromosomes, including 11 homozygotes (gnomAD v2.1 and v3.1 non-v2 datasets). The variant was reported predominantly within the African or African-American subpopulation at a frequency of 0.014 (including 7 homozygotes), the observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.4-fold of the estimated maximal expected allele frequency for a pathogenic variant in ASS1 causing Citrullinemia Type I phenotype (0.0041), strongly suggesting that the variant is a benign polymorphism. Though the variant, c.323G>T, has been reported in the literature in individuals affected with Citrullinemia Type I (Vilaseca_2001, Haberle_2002, Tabor_2014,), these reports do not provide unequivocal conclusions about association of the variant with Citrullinemia Type I. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), likely benign (n=3) / benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

Citrullinemia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ASS1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;D;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.4	L;L;L;.;.
MutationTaster	Benign	0.82	A;A;A;A
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.0020	B;B;B;.;.
Vest4		0.66
MVP		0.94
MPC		0.33
ClinPred		0.025	T
GERP RS		4.0
Varity_R		0.46
gMVP		0.54

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: rs35269064; hg19: chr9-133333936;