rs967485459

Variant names:

• chr16-70270280-C-T
• rs967485459
• NM_001605.3:c.732G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001605.3(AARS1):​c.732G>A​(p.Leu244Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 31)
• Consequence: AARS1 NM_001605.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

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]

AARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2N

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• developmental and epileptic encephalopathy, 29

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• trichothiodystrophy 8, nonphotosensitive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-70270280-C-T is Benign according to our data. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-70270280-C-T is described in CliVar as Likely_benign. Clinvar id is 476743.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS1	NM_001605.3	c.732G>A	p.Leu244Leu	synonymous_variant	Exon 6 of 21	ENST00000261772.13	NP_001596.2
AARS1	XM_047433666.1	c.732G>A	p.Leu244Leu	synonymous_variant	Exon 6 of 16		XP_047289622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13	c.732G>A	p.Leu244Leu	synonymous_variant	Exon 6 of 21	1	NM_001605.3	ENSP00000261772.8

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

African (AFR) AF: 0.0000724 AC: 3 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Benign:1

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.37
CADD	Benign	8.8
DANN	Benign	0.75
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs967485459; hg19: chr16-70304183;