9-130450341-C-T

Position:

• chr9-130450341-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000050.4(ASS1):​c.-6+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 987,336 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (12 hom.)
• Consequence: ASS1 NM_000050.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001812
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.296

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-130450341-C-T is Benign according to our data. Variant chr9-130450341-C-T is described in ClinVar as [Benign]. Clinvar id is 381450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1532/152318) while in subpopulation AFR AF= 0.0346 (1437/41562). AF 95% confidence interval is 0.0331. There are 26 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4	c.-5-1883C>T		intron_variant		ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.-6+8C>T		splice_region_variant, intron_variant			NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.-5-1883C>T		intron_variant		1	NM_054012.4	ENSP00000253004.6
ASS1	ENST00000372393.7	c.-6+8C>T		splice_region_variant, intron_variant		5		ENSP00000361469.2
ASS1	ENST00000372394.5	c.-447-1261C>T		intron_variant		2		ENSP00000361471.1
ASS1	ENST00000422569.5	c.-5-1883C>T		intron_variant		5		ENSP00000394212.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1529 AN: 152200 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

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: 0.000265

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00114 AC: 951 AN: 835018 Hom.: 12 Cov.: 29 AF XY: 0.00107 AC XY: 413 AN XY: 385746

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.00301

Gnomad4 ASJ exome AF: 0.000194

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000356

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152318 Hom.: 26 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74480

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00913 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 10, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Citrullinemia type I Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs12004384; hg19: chr9-133325728;