rs12004384

Variant names:

• chr9-130450341-C-G
• rs12004384
• NM_054012.4:c.-5-1883C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-130450341-C-G
• chr9-130450341-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_054012.4(ASS1):​c.-5-1883C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000024 in 835,024 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Scores: Splicing: ADA: 0.0001597
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-1883C>G		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-6+8C>G		splice_region_variant, intron_variant	Intron 2 of 15		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.-5-1883C>G		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000372393.7	c.-6+8C>G		splice_region_variant, intron_variant	Intron 2 of 15	5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.-447-1261C>G		intron_variant	Intron 1 of 15	2		ENSP00000361471.1
ASS1	ENST00000422569.5	c.-5-1883C>G		intron_variant	Intron 1 of 7	5		ENSP00000394212.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000240 AC: 2 AN: 835024 Hom.: 0 Cov.: 29 AF XY: 0.00000518 AC XY: 2 AN XY: 385746

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15834

American (AMR) AF: 0.00 AC: 0 AN: 998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5160

East Asian (EAS) AF: 0.00 AC: 0 AN: 3642

South Asian (SAS) AF: 0.00 AC: 0 AN: 16498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2276

European-Non Finnish (NFE) AF: 0.00000262 AC: 2 AN: 762260

Other (OTH) AF: 0.00 AC: 0 AN: 27484

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.45
PhyloP100		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0
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: rs12004384; hg19: chr9-133325728;