rs1057484

Variant names:

• chr9-130489370-T-C
• rs1057484
• NM_054012.4:c.876T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_054012.4(ASS1):​c.876T>C​(p.His292His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 1,613,790 control chromosomes in the GnomAD database, including 8,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (911 hom., cov: 31)
  • Exomes 𝑓: 0.098 (7725 hom.)
• Consequence: ASS1 NM_054012.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.181
• Publications: 15 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, G2P, Myriad Women’s Health
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-130489370-T-C is Benign according to our data. Variant chr9-130489370-T-C is described in ClinVar as Benign. ClinVar VariationId is 92376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.181 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054012.4. 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
	ASS1	NM_054012.4	MANE Select	c.876T>C	p.His292His	synonymous	Exon 12 of 15	NP_446464.1	Q5T6L4
	ASS1	NM_000050.4		c.876T>C	p.His292His	synonymous	Exon 13 of 16	NP_000041.2	P00966

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	ENST00000352480.10	TSL:1 MANE Select	c.876T>C	p.His292His	synonymous	Exon 12 of 15	ENSP00000253004.6	P00966
	ASS1	ENST00000852201.1		c.1071T>C	p.His357His	synonymous	Exon 13 of 16	ENSP00000522260.1
	ASS1	ENST00000852207.1		c.999T>C	p.His333His	synonymous	Exon 13 of 16	ENSP00000522266.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15711 AN: 151886 Hom.: 913 Cov.: 31

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0622

Gnomad ASJ AF: 0.0704

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0642

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0825

GnomAD2 exomes AF: 0.0914 AC: 22983 AN: 251440 AF XY: 0.0927

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0472

Gnomad ASJ exome AF: 0.0691

Gnomad EAS exome AF: 0.00158

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0985

GnomAD4 exome AF: 0.0979 AC: 143143 AN: 1461786 Hom.: 7725 Cov.: 34 AF XY: 0.0974 AC XY: 70805 AN XY: 727204

African (AFR) AF: 0.117 AC: 3908 AN: 33474

American (AMR) AF: 0.0495 AC: 2212 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0693 AC: 1810 AN: 26136

East Asian (EAS) AF: 0.00106 AC: 42 AN: 39700

South Asian (SAS) AF: 0.0685 AC: 5910 AN: 86258

European-Finnish (FIN) AF: 0.174 AC: 9291 AN: 53362

Middle Eastern (MID) AF: 0.0956 AC: 551 AN: 5766

European-Non Finnish (NFE) AF: 0.102 AC: 113819 AN: 1111974

Other (OTH) AF: 0.0927 AC: 5600 AN: 60394

GnomAD4 genome AF: 0.103 AC: 15723 AN: 152004 Hom.: 911 Cov.: 31 AF XY: 0.105 AC XY: 7817 AN XY: 74294

African (AFR) AF: 0.111 AC: 4608 AN: 41452

American (AMR) AF: 0.0621 AC: 948 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 244 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5172

South Asian (SAS) AF: 0.0636 AC: 306 AN: 4808

European-Finnish (FIN) AF: 0.185 AC: 1949 AN: 10552

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7382 AN: 67968

Other (OTH) AF: 0.0816 AC: 172 AN: 2108

Alfa AF: 0.105 Hom.: 390

Bravo AF: 0.0951

Asia WGS AF: 0.0430 AC: 152 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.102

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Citrullinemia type I (4)
-	-	4	not specified (4)
-	-	1	Citrullinemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.5
DANN	Benign	0.53
PhyloP100		-0.18
Mutation Taster		=99/1	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: rs1057484; hg19: chr9-133364757; COSMIC: COSV61689835;