NM_054012.4:c.-5-300G>A

Variant names:

• chr9-130451924-G-A
• rs114084616
• NM_054012.4:c.-5-300G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_054012.4(ASS1):​c.-5-300G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 563,280 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0310
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 9-130451924-G-A is Benign according to our data. Variant chr9-130451924-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1204545.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00677 (1032/152334) while in subpopulation AFR AF = 0.0237 (985/41576). AF 95% confidence interval is 0.0225. There are 15 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-300G>A		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-5-300G>A		intron_variant	Intron 2 of 15		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.-5-300G>A		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000372394.5	c.-125G>A		5_prime_UTR_variant	Exon 2 of 16	2		ENSP00000361471.1
ASS1	ENST00000372393.7	c.-5-300G>A		intron_variant	Intron 2 of 15	5		ENSP00000361469.2
ASS1	ENST00000422569.5	c.-5-300G>A		intron_variant	Intron 1 of 7	5		ENSP00000394212.1

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1031 AN: 152216 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00159 AC: 214 AN: 134696 AF XY: 0.00132

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000190

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.000482

GnomAD4 exome AF: 0.00102 AC: 418 AN: 410946 Hom.: 7 Cov.: 0 AF XY: 0.000816 AC XY: 185 AN XY: 226830

African (AFR) AF: 0.0238 AC: 294 AN: 12356

American (AMR) AF: 0.00148 AC: 45 AN: 30334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15334

East Asian (EAS) AF: 0.000107 AC: 2 AN: 18730

South Asian (SAS) AF: 0.0000659 AC: 4 AN: 60656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20254

Middle Eastern (MID) AF: 0.000590 AC: 2 AN: 3388

European-Non Finnish (NFE) AF: 0.0000920 AC: 21 AN: 228162

Other (OTH) AF: 0.00230 AC: 50 AN: 21732

GnomAD4 genome AF: 0.00677 AC: 1032 AN: 152334 Hom.: 15 Cov.: 33 AF XY: 0.00661 AC XY: 492 AN XY: 74486

African (AFR) AF: 0.0237 AC: 985 AN: 41576

American (AMR) AF: 0.00176 AC: 27 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00792 Hom.: 2

Bravo AF: 0.00773

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 17, 2018

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	-0.65
CADD	Benign	0.46
DANN	Benign	0.74
PhyloP100		-0.031
PromoterAI		-0.23	Neutral
Mutation Taster		=300/0	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: rs114084616; hg19: chr9-133327311;