9-130480487-A-G

Variant names:

• chr9-130480487-A-G
• rs1215940
• NM_054012.4:c.838+38A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_054012.4(ASS1):​c.838+38A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,608,404 control chromosomes in the GnomAD database, including 776,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (63805 hom., cov: 35)
  • Exomes 𝑓: 0.99 (712503 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.580
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-130480487-A-G is Benign according to our data. Variant chr9-130480487-A-G is described in ClinVar as Benign. ClinVar VariationId is 254749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 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.838+38A>G		intron	N/A	NP_446464.1	Q5T6L4
	ASS1	NM_000050.4		c.838+38A>G		intron	N/A	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.838+38A>G		intron	N/A	ENSP00000253004.6	P00966
	ASS1	ENST00000852201.1		c.1033+38A>G		intron	N/A	ENSP00000522260.1
	ASS1	ENST00000852207.1		c.838+38A>G		intron	N/A	ENSP00000522266.1

Frequencies

GnomAD3 genomes AF: 0.905 AC: 137638 AN: 152152 Hom.: 63771 Cov.: 35

Gnomad AFR AF: 0.677

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.959

Gnomad ASJ AF: 0.965

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.996

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.925

GnomAD2 exomes AF: 0.973 AC: 238465 AN: 245134 AF XY: 0.979

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.969

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.981

GnomAD4 exome AF: 0.988 AC: 1438498 AN: 1456134 Hom.: 712503 Cov.: 35 AF XY: 0.989 AC XY: 716522 AN XY: 724340

African (AFR) AF: 0.659 AC: 21977 AN: 33362

American (AMR) AF: 0.980 AC: 43501 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.969 AC: 25259 AN: 26054

East Asian (EAS) AF: 1.00 AC: 39637 AN: 39638

South Asian (SAS) AF: 0.997 AC: 85465 AN: 85702

European-Finnish (FIN) AF: 1.00 AC: 52398 AN: 52410

Middle Eastern (MID) AF: 0.976 AC: 5326 AN: 5456

European-Non Finnish (NFE) AF: 0.998 AC: 1106378 AN: 1108922

Other (OTH) AF: 0.973 AC: 58557 AN: 60180

GnomAD4 genome AF: 0.904 AC: 137727 AN: 152270 Hom.: 63805 Cov.: 35 AF XY: 0.908 AC XY: 67592 AN XY: 74462

African (AFR) AF: 0.677 AC: 28109 AN: 41510

American (AMR) AF: 0.959 AC: 14680 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.965 AC: 3352 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5174 AN: 5174

South Asian (SAS) AF: 0.996 AC: 4805 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10630 AN: 10630

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67824 AN: 68026

Other (OTH) AF: 0.926 AC: 1958 AN: 2114

Alfa AF: 0.936 Hom.: 14111

Bravo AF: 0.889

Asia WGS AF: 0.984 AC: 3421 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Citrullinemia type I (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.29
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1215940; hg19: chr9-133355874;