16-70252647-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001605.3(AARS1):c.*74A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,549,306 control chromosomes in the GnomAD database, including 3,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (300 hom., cov: 33)
  • Exomes 𝑓: 0.069 (3629 hom.)
• Consequence: AARS1 NM_001605.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.417

Genes affected

AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-70252647-T-A is Benign according to our data. Variant chr16-70252647-T-A is described in ClinVar as [Benign]. Clinvar id is 320323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70252647-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS1	NM_001605.3	c.*74A>T		3_prime_UTR_variant	21/21	ENST00000261772.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS1	ENST00000261772.13	c.*74A>T		3_prime_UTR_variant	21/21	1	NM_001605.3	P1

Frequencies

GnomAD3 genomes AF: 0.0594 AC: 9041 AN: 152100 Hom.: 300 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0604

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0667

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.0746

GnomAD4 exome AF: 0.0685 AC: 95702 AN: 1397088 Hom.: 3629 Cov.: 23 AF XY: 0.0688 AC XY: 48102 AN XY: 698702

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0448

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.0722

Gnomad4 FIN exome AF: 0.0724

Gnomad4 NFE exome AF: 0.0725

Gnomad4 OTH exome AF: 0.0696

GnomAD4 genome AF: 0.0594 AC: 9038 AN: 152218 Hom.: 300 Cov.: 33 AF XY: 0.0603 AC XY: 4486 AN XY: 74398

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.0604

Gnomad4 ASJ AF: 0.0585

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0670

Gnomad4 FIN AF: 0.0781

Gnomad4 NFE AF: 0.0722

Gnomad4 OTH AF: 0.0734

Alfa AF: 0.0334 Hom.: 24

Bravo AF: 0.0574

Asia WGS AF: 0.0290 AC: 102 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

- -

Charcot-Marie-Tooth disease axonal type 2N Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.3
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs11537663; hg19: chr16-70286550; COSMIC: COSV55747087; COSMIC: COSV55747087;