9-130471523-C-T

Variant names:

• chr9-130471523-C-T
• rs77343702
• NM_054012.4:c.597+8C>T

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.597+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00896 in 1,613,784 control chromosomes in the GnomAD database, including 977 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (516 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (461 hom.)
• Consequence: ASS1 NM_054012.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001715
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0630
• Publications: 3 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=-0.75).
• BP6: Variant 9-130471523-C-T is Benign according to our data. Variant chr9-130471523-C-T is described in ClinVar as Benign. ClinVar VariationId is 254747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 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.597+8C>T		splice_region intron	N/A	NP_446464.1	Q5T6L4
	ASS1	NM_000050.4		c.597+8C>T		splice_region 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.597+8C>T		splice_region intron	N/A	ENSP00000253004.6	P00966
	ASS1	ENST00000852201.1		c.792+8C>T		splice_region intron	N/A	ENSP00000522260.1
	ASS1	ENST00000852207.1		c.597+8C>T		splice_region intron	N/A	ENSP00000522266.1

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6906 AN: 152142 Hom.: 513 Cov.: 33

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0122 AC: 3078 AN: 251386 AF XY: 0.00912

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.00963

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000871

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00515 AC: 7533 AN: 1461524 Hom.: 461 Cov.: 31 AF XY: 0.00448 AC XY: 3255 AN XY: 727086

African (AFR) AF: 0.162 AC: 5424 AN: 33458

American (AMR) AF: 0.0116 AC: 518 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5764

European-Non Finnish (NFE) AF: 0.000680 AC: 756 AN: 1111734

Other (OTH) AF: 0.0114 AC: 689 AN: 60380

GnomAD4 genome AF: 0.0455 AC: 6926 AN: 152260 Hom.: 516 Cov.: 33 AF XY: 0.0437 AC XY: 3251 AN XY: 74454

African (AFR) AF: 0.156 AC: 6490 AN: 41522

American (AMR) AF: 0.0187 AC: 287 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68010

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0434 Hom.: 382

Bravo AF: 0.0515

Asia WGS AF: 0.0140 AC: 49 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)
-	-	2	not specified (2)
-	-	1	Citrullinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.4
DANN	Benign	0.49
PhyloP100		-0.063
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		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: rs77343702; hg19: chr9-133346910; COSMIC: COSV61688819; COSMIC: COSV61688819;