rs73541961

Variant names:

• chr9-130454394-A-G
• rs73541961
• NM_054012.4:c.174+21A>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.174+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,611,758 control chromosomes in the GnomAD database, including 1,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (724 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (651 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.28
• 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, 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-130454394-A-G is Benign according to our data. Variant chr9-130454394-A-G is described in ClinVar as Benign. ClinVar VariationId is 254743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	NM_054012.4	MANE Select	c.174+21A>G		intron	N/A	NP_446464.1
	ASS1	NM_000050.4		c.174+21A>G		intron	N/A	NP_000041.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	ENST00000352480.10	TSL:1 MANE Select	c.174+21A>G		intron	N/A	ENSP00000253004.6
	ASS1	ENST00000372393.7	TSL:5	c.174+21A>G		intron	N/A	ENSP00000361469.2
	ASS1	ENST00000372394.5	TSL:2	c.174+21A>G		intron	N/A	ENSP00000361471.1

Frequencies

GnomAD3 genomes AF: 0.0518 AC: 7884 AN: 152122 Hom.: 718 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0374

GnomAD2 exomes AF: 0.0153 AC: 3766 AN: 246220 AF XY: 0.0121

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000963

Gnomad OTH exome AF: 0.00895

GnomAD4 exome AF: 0.00656 AC: 9571 AN: 1459518 Hom.: 651 Cov.: 31 AF XY: 0.00613 AC XY: 4453 AN XY: 725926

African (AFR) AF: 0.181 AC: 6050 AN: 33404

American (AMR) AF: 0.0122 AC: 541 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26064

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39644

South Asian (SAS) AF: 0.0125 AC: 1077 AN: 85846

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53288

Middle Eastern (MID) AF: 0.0193 AC: 111 AN: 5752

European-Non Finnish (NFE) AF: 0.000794 AC: 882 AN: 1110758

Other (OTH) AF: 0.0146 AC: 879 AN: 60320

GnomAD4 genome AF: 0.0520 AC: 7915 AN: 152240 Hom.: 724 Cov.: 32 AF XY: 0.0501 AC XY: 3730 AN XY: 74446

African (AFR) AF: 0.178 AC: 7391 AN: 41506

American (AMR) AF: 0.0206 AC: 315 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68016

Other (OTH) AF: 0.0370 AC: 78 AN: 2110

Alfa AF: 0.0298 Hom.: 57

Bravo AF: 0.0594

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.041
DANN	Benign	0.63
PhyloP100		-2.3
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: rs73541961; hg19: chr9-133329781;