NM_001605.3:c.2287-95A>G

Variant names:

• chr16-70254829-T-C
• rs7205918
• NM_001605.3:c.2287-95A>G

Variant summary

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

The NM_001605.3(AARS1):​c.2287-95A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 812,416 control chromosomes in the GnomAD database, including 2,943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (2036 hom., cov: 32)
  • Exomes 𝑓: 0.011 (907 hom.)
• Consequence: AARS1 NM_001605.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 4 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

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

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• AARS1-related leukoencephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• trichothiodystrophy 8, nonphotosensitive

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-70254829-T-C is Benign according to our data. Variant chr16-70254829-T-C is described in ClinVar as Benign. ClinVar VariationId is 676184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001605.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AARS1	NM_001605.3	MANE Select	c.2287-95A>G		intron	N/A	NP_001596.2	P49588-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AARS1	ENST00000261772.13	TSL:1 MANE Select	c.2287-95A>G		intron	N/A	ENSP00000261772.8	P49588-1
	AARS1	ENST00000565361.3	TSL:5	c.2287-95A>G		intron	N/A	ENSP00000455360.3	H3BPK7
	AARS1	ENST00000896288.1		c.2287-95A>G		intron	N/A	ENSP00000566347.1

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 13698 AN: 152126 Hom.: 2026 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.0676

GnomAD4 exome AF: 0.0109 AC: 7222 AN: 660174 Hom.: 907 AF XY: 0.00904 AC XY: 3178 AN XY: 351398

African (AFR) AF: 0.299 AC: 5295 AN: 17684

American (AMR) AF: 0.0164 AC: 576 AN: 35136

Ashkenazi Jewish (ASJ) AF: 0.0000490 AC: 1 AN: 20396

East Asian (EAS) AF: 0.0000914 AC: 3 AN: 32810

South Asian (SAS) AF: 0.00248 AC: 163 AN: 65696

European-Finnish (FIN) AF: 0.0000232 AC: 1 AN: 43124

Middle Eastern (MID) AF: 0.0146 AC: 43 AN: 2942

European-Non Finnish (NFE) AF: 0.000817 AC: 334 AN: 408936

Other (OTH) AF: 0.0241 AC: 806 AN: 33450

GnomAD4 genome AF: 0.0903 AC: 13742 AN: 152242 Hom.: 2036 Cov.: 32 AF XY: 0.0871 AC XY: 6482 AN XY: 74452

African (AFR) AF: 0.310 AC: 12887 AN: 41510

American (AMR) AF: 0.0380 AC: 581 AN: 15300

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68026

Other (OTH) AF: 0.0693 AC: 146 AN: 2108

Alfa AF: 0.0424 Hom.: 147

Bravo AF: 0.101

Asia WGS AF: 0.0320 AC: 111 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.053
DANN	Benign	0.35
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs7205918; hg19: chr16-70288732;