NM_054012.4:c.-5-2139T>C

Variant names:

• chr9-130450085-T-C
• rs4740158
• NM_054012.4:c.-5-2139T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_054012.4(ASS1):​c.-5-2139T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 152,178 control chromosomes in the GnomAD database, including 46,055 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (46055 hom., cov: 33)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.759
• Publications: 9 publications found

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]

ASS1 Gene-Disease associations (from GenCC):

• citrullinemia type I

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• acute neonatal citrullinemia type I

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• adult-onset citrullinemia type I

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-2139T>C		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-67-187T>C		intron_variant	Intron 1 of 15		NP_000041.2
LOC124902349	XR_007061925.1	n.*130T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.-5-2139T>C		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000372393.7	c.-67-187T>C		intron_variant	Intron 1 of 15	5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.-447-1517T>C		intron_variant	Intron 1 of 15	2		ENSP00000361471.1
ASS1	ENST00000422569.5	c.-5-2139T>C		intron_variant	Intron 1 of 7	5		ENSP00000394212.1

Frequencies

GnomAD3 genomes AF: 0.776 AC: 118041 AN: 152060 Hom.: 46010 Cov.: 33

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.734

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.774

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.776 AC: 118148 AN: 152178 Hom.: 46055 Cov.: 33 AF XY: 0.777 AC XY: 57816 AN XY: 74392

African (AFR) AF: 0.816 AC: 33893 AN: 41522

American (AMR) AF: 0.741 AC: 11336 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2584 AN: 3470

East Asian (EAS) AF: 0.900 AC: 4648 AN: 5164

South Asian (SAS) AF: 0.718 AC: 3462 AN: 4822

European-Finnish (FIN) AF: 0.801 AC: 8478 AN: 10586

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.753 AC: 51225 AN: 68002

Other (OTH) AF: 0.774 AC: 1634 AN: 2112

Alfa AF: 0.762 Hom.: 82858

Bravo AF: 0.775

Asia WGS AF: 0.792 AC: 2755 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.31
DANN	Benign	0.48
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4740158; hg19: chr9-133325472;