rs73541957

Variant names:

• chr9-130454295-T-G
• rs73541957
• NM_054012.4:c.106-10T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_054012.4(ASS1):​c.106-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000982 in 1,609,626 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Scores: Splicing: ADA: 0.1707
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.16
• Publications: 1 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=-0.72).
• BP6: Variant 9-130454295-T-G is Benign according to our data. Variant chr9-130454295-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00546 (832/152370) while in subpopulation AFR AF = 0.0193 (801/41588). AF 95% confidence interval is 0.0182. There are 10 homozygotes in GnomAd4. There are 407 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.106-10T>G		intron	N/A	NP_446464.1	Q5T6L4
	ASS1	NM_000050.4		c.106-10T>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.106-10T>G		intron	N/A	ENSP00000253004.6	P00966
	ASS1	ENST00000852201.1		c.106-10T>G		intron	N/A	ENSP00000522260.1
	ASS1	ENST00000852207.1		c.106-10T>G		intron	N/A	ENSP00000522266.1

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 832 AN: 152252 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00132 AC: 323 AN: 245510 AF XY: 0.00104

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.000995

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000514 AC: 749 AN: 1457256 Hom.: 6 Cov.: 31 AF XY: 0.000454 AC XY: 329 AN XY: 724668

African (AFR) AF: 0.0186 AC: 622 AN: 33356

American (AMR) AF: 0.000968 AC: 43 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.000448 AC: 2 AN: 4462

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110492

Other (OTH) AF: 0.00128 AC: 77 AN: 60106

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152370 Hom.: 10 Cov.: 33 AF XY: 0.00546 AC XY: 407 AN XY: 74504

African (AFR) AF: 0.0193 AC: 801 AN: 41588

American (AMR) AF: 0.00163 AC: 25 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00441 Hom.: 2

Bravo AF: 0.00624

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Citrullinemia type I (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Citrullinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.17
dbscSNV1_RF	Benign	0.38
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: rs73541957; hg19: chr9-133329682;