9-130445039-G-C

Variant names:

• chr9-130445039-G-C
• rs151254686
• NM_054012.4:c.-6+44G>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.-6+44G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 576,392 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 33)
  • Exomes 𝑓: 0.020 (91 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.733
• Publications: 0 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=-0.78).
• BP6: Variant 9-130445039-G-C is Benign according to our data. Variant chr9-130445039-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1328790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1925/152346) while in subpopulation NFE AF = 0.0205 (1398/68032). AF 95% confidence interval is 0.0197. There are 21 homozygotes in GnomAd4. There are 905 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-6+44G>C		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-68+44G>C		intron_variant	Intron 1 of 15		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.-6+44G>C		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000422569.5	c.-165G>C		5_prime_UTR_variant	Exon 1 of 8	5		ENSP00000394212.1
ASS1	ENST00000372393.7	c.-68+44G>C		intron_variant	Intron 1 of 15	5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.-448+44G>C		intron_variant	Intron 1 of 15	2		ENSP00000361471.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1925 AN: 152228 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.0203 AC: 8601 AN: 424046 Hom.: 91 Cov.: 5 AF XY: 0.0204 AC XY: 4087 AN XY: 199972

African (AFR) AF: 0.00241 AC: 19 AN: 7872

American (AMR) AF: 0.00652 AC: 3 AN: 460

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 38 AN: 2698

East Asian (EAS) AF: 0.00 AC: 0 AN: 1772

South Asian (SAS) AF: 0.0195 AC: 164 AN: 8418

European-Finnish (FIN) AF: 0.00833 AC: 1 AN: 120

Middle Eastern (MID) AF: 0.0187 AC: 17 AN: 910

European-Non Finnish (NFE) AF: 0.0210 AC: 8144 AN: 387928

Other (OTH) AF: 0.0155 AC: 215 AN: 13868

GnomAD4 genome AF: 0.0126 AC: 1925 AN: 152346 Hom.: 21 Cov.: 33 AF XY: 0.0121 AC XY: 905 AN XY: 74500

African (AFR) AF: 0.00344 AC: 143 AN: 41582

American (AMR) AF: 0.00477 AC: 73 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4834

European-Finnish (FIN) AF: 0.0143 AC: 152 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0205 AC: 1398 AN: 68032

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.0155 Hom.: 0

Bravo AF: 0.0113

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 17, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.2
DANN	Benign	0.45
PhyloP100		0.73
PromoterAI		-0.032	Neutral
Mutation Taster		=100/0	polymorphism

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: rs151254686; hg19: chr9-133320426;