9-130445062-A-C

Variant names:

• chr9-130445062-A-C
• rs6597680
• NM_054012.4:c.-6+67A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_054012.4(ASS1):​c.-6+67A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 764,986 control chromosomes in the GnomAD database, including 106,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20706 hom., cov: 34)
  • Exomes 𝑓: 0.53 (85466 hom.)
• Consequence: ASS1 NM_054012.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.420
• 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=-0.8).
• BP6: Variant 9-130445062-A-C is Benign according to our data. Variant chr9-130445062-A-C is described in ClinVar as [Benign]. Clinvar id is 1249407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-6+67A>C		intron_variant	Intron 1 of 14	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-68+67A>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+67A>C		intron_variant	Intron 1 of 14	1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000422569.5	c.-142A>C		5_prime_UTR_variant	Exon 1 of 8	5		ENSP00000394212.1
ASS1	ENST00000372393.7	c.-68+67A>C		intron_variant	Intron 1 of 15	5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.-448+67A>C		intron_variant	Intron 1 of 15	2		ENSP00000361471.1

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79097 AN: 151980 Hom.: 20673 Cov.: 34

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.502

GnomAD4 exome AF: 0.527 AC: 323065 AN: 612890 Hom.: 85466 Cov.: 7 AF XY: 0.528 AC XY: 151160 AN XY: 286540

African (AFR) AF: 0.553 AC: 6368 AN: 11522

American (AMR) AF: 0.552 AC: 379 AN: 686

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1421 AN: 3812

East Asian (EAS) AF: 0.535 AC: 1392 AN: 2604

South Asian (SAS) AF: 0.431 AC: 5258 AN: 12208

European-Finnish (FIN) AF: 0.589 AC: 106 AN: 180

Middle Eastern (MID) AF: 0.426 AC: 530 AN: 1244

European-Non Finnish (NFE) AF: 0.531 AC: 297435 AN: 560622

Other (OTH) AF: 0.508 AC: 10176 AN: 20012

GnomAD4 genome AF: 0.521 AC: 79189 AN: 152096 Hom.: 20706 Cov.: 34 AF XY: 0.519 AC XY: 38585 AN XY: 74356

African (AFR) AF: 0.560 AC: 23269 AN: 41524

American (AMR) AF: 0.528 AC: 8072 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1251 AN: 3468

East Asian (EAS) AF: 0.537 AC: 2755 AN: 5128

South Asian (SAS) AF: 0.421 AC: 2024 AN: 4812

European-Finnish (FIN) AF: 0.540 AC: 5724 AN: 10598

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34427 AN: 67954

Other (OTH) AF: 0.505 AC: 1067 AN: 2112

Alfa AF: 0.502 Hom.: 2979

Bravo AF: 0.523

Asia WGS AF: 0.517 AC: 1796 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: 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	-0.80
CADD	Benign	6.8
DANN	Benign	0.79
PhyloP100		-0.42
PromoterAI		0.020	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs6597680; hg19: chr9-133320449;