NM_054012.4:c.-5-215G>A

Variant names:

• chr9-130452009-G-A
• rs150904366
• NM_054012.4:c.-5-215G>A

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.-5-215G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 677,806 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (10 hom., cov: 33)
  • Exomes 𝑓: 0.012 (80 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.351
• 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, 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=-0.64).
• BP6: Variant 9-130452009-G-A is Benign according to our data. Variant chr9-130452009-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1207249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00958 (1459/152332) while in subpopulation AMR AF = 0.0127 (194/15310). AF 95% confidence interval is 0.0115. There are 10 homozygotes in GnomAd4. There are 698 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-215G>A		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-5-215G>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.-5-215G>A		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes AF: 0.00959 AC: 1459 AN: 152214 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0113 AC: 1546 AN: 136468 AF XY: 0.0112

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00905

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0118 AC: 6177 AN: 525474 Hom.: 80 Cov.: 0 AF XY: 0.0114 AC XY: 3245 AN XY: 285182

African (AFR) AF: 0.00237 AC: 36 AN: 15216

American (AMR) AF: 0.00765 AC: 259 AN: 33850

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 951 AN: 19158

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 29986

South Asian (SAS) AF: 0.00318 AC: 196 AN: 61698

European-Finnish (FIN) AF: 0.00576 AC: 183 AN: 31754

Middle Eastern (MID) AF: 0.0206 AC: 81 AN: 3928

European-Non Finnish (NFE) AF: 0.0135 AC: 4052 AN: 300900

Other (OTH) AF: 0.0144 AC: 418 AN: 28984

GnomAD4 genome AF: 0.00958 AC: 1459 AN: 152332 Hom.: 10 Cov.: 33 AF XY: 0.00937 AC XY: 698 AN XY: 74490

African (AFR) AF: 0.00255 AC: 106 AN: 41586

American (AMR) AF: 0.0127 AC: 194 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0122 AC: 828 AN: 68030

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0159 Hom.: 9

Bravo AF: 0.00992

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.8
DANN	Benign	0.62
PhyloP100		-0.35
PromoterAI		-0.034	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: rs150904366; hg19: chr9-133327396;