rs116103138

Variant names:

• chr9-130464105-T-C
• rs116103138
• NM_054012.4:c.364-6T>C

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.364-6T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00179 in 1,613,974 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: ASS1 NM_054012.4 splice_region, intron
• Scores: Splicing: ADA: 0.002996
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.65
• 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=-0.58).
• BP6: Variant 9-130464105-T-C is Benign according to our data. Variant chr9-130464105-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254745.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 = 0.0082 (1247/152116) while in subpopulation AFR AF = 0.0281 (1164/41486). AF 95% confidence interval is 0.0267. There are 12 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.364-6T>C		splice_region intron	N/A	NP_446464.1	Q5T6L4
	ASS1	NM_000050.4		c.364-6T>C		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.364-6T>C		splice_region intron	N/A	ENSP00000253004.6	P00966
	ASS1	ENST00000852201.1		c.364-6T>C		splice_region intron	N/A	ENSP00000522260.1
	ASS1	ENST00000852207.1		c.364-6T>C		splice_region intron	N/A	ENSP00000522266.1

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1246 AN: 151998 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

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: 0.000206

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00262 AC: 658 AN: 251418 AF XY: 0.00207

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00112 AC: 1640 AN: 1461858 Hom.: 22 Cov.: 32 AF XY: 0.000987 AC XY: 718 AN XY: 727232

African (AFR) AF: 0.0300 AC: 1003 AN: 33474

American (AMR) AF: 0.00333 AC: 149 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.000265 AC: 295 AN: 1111988

Other (OTH) AF: 0.00247 AC: 149 AN: 60396

GnomAD4 genome AF: 0.00820 AC: 1247 AN: 152116 Hom.: 12 Cov.: 33 AF XY: 0.00803 AC XY: 597 AN XY: 74364

African (AFR) AF: 0.0281 AC: 1164 AN: 41486

American (AMR) AF: 0.00373 AC: 57 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67980

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00446 Hom.: 7

Bravo AF: 0.00958

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.8
DANN	Benign	0.73
PhyloP100		3.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116103138; hg19: chr9-133339492;