rs74024185

chr16-70271778-T-C

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.671+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,802 control chromosomes in the GnomAD database, including 2,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (1276 hom., cov: 31)
  • Exomes 𝑓: 0.0072 (1159 hom.)
• Consequence: AARS1 NM_001605.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.1088
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.399

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=-0.74).
• BP6: Variant 16-70271778-T-C is Benign according to our data. Variant chr16-70271778-T-C is described in ClinVar as [Benign]. Clinvar id is 320351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70271778-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS1	NM_001605.3	c.671+3A>G		splice_donor_region_variant, intron_variant		ENST00000261772.13
AARS1	XM_047433666.1	c.671+3A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS1	ENST00000261772.13	c.671+3A>G		splice_donor_region_variant, intron_variant		1	NM_001605.3	P1

Frequencies

GnomAD3 genomes AF: 0.0710 AC: 10792 AN: 151940 Hom.: 1274 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0180 AC: 4524 AN: 251426 Hom.: 539 AF XY: 0.0136 AC XY: 1850 AN XY: 135898

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00716 AC: 10468 AN: 1461744 Hom.: 1159 Cov.: 31 AF XY: 0.00623 AC XY: 4533 AN XY: 727186

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000329

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0710 AC: 10802 AN: 152058 Hom.: 1276 Cov.: 31 AF XY: 0.0690 AC XY: 5124 AN XY: 74290

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0324 Hom.: 256

Bravo AF: 0.0791

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	16
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.040		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: rs74024185; hg19: chr16-70305681;