rs117598688

Variant names:

• chr16-70265046-G-A
• rs117598688
• NM_001605.3:c.1404C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001605.3(AARS1):​c.1404C>T​(p.Tyr468Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,018 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (3 hom., cov: 31)
  • Exomes 𝑓: 0.010 (126 hom.)
• Consequence: AARS1 NM_001605.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.38
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-70265046-G-A is Benign according to our data. Variant chr16-70265046-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00683 (1039/152214) while in subpopulation SAS AF = 0.0191 (92/4814). AF 95% confidence interval is 0.016. There are 3 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

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.1404C>T	p.Tyr468Tyr	synonymous	Exon 11 of 21	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.1404C>T	p.Tyr468Tyr	synonymous	Exon 11 of 21	ENSP00000261772.8	P49588-1
	AARS1	ENST00000565361.3	TSL:5	c.1404C>T	p.Tyr468Tyr	synonymous	Exon 11 of 22	ENSP00000455360.3	H3BPK7
	AARS1	ENST00000896288.1		c.1404C>T	p.Tyr468Tyr	synonymous	Exon 11 of 22	ENSP00000566347.1

Frequencies

GnomAD3 genomes AF: 0.00684 AC: 1040 AN: 152098 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00978

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00907 AC: 2281 AN: 251478 AF XY: 0.0101

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00962

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0104 AC: 15223 AN: 1461804 Hom.: 126 Cov.: 32 AF XY: 0.0109 AC XY: 7892 AN XY: 727202

African (AFR) AF: 0.00191 AC: 64 AN: 33476

American (AMR) AF: 0.00324 AC: 145 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 526 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0237 AC: 2043 AN: 86258

European-Finnish (FIN) AF: 0.00331 AC: 177 AN: 53394

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5762

European-Non Finnish (NFE) AF: 0.0104 AC: 11545 AN: 1111976

Other (OTH) AF: 0.0103 AC: 620 AN: 60386

GnomAD4 genome AF: 0.00683 AC: 1039 AN: 152214 Hom.: 3 Cov.: 31 AF XY: 0.00650 AC XY: 484 AN XY: 74422

African (AFR) AF: 0.00193 AC: 80 AN: 41534

American (AMR) AF: 0.00393 AC: 60 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4814

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00978 AC: 665 AN: 68012

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00785 Hom.: 5

Bravo AF: 0.00668

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.00942

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Charcot-Marie-Tooth disease axonal type 2N (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2N;C4225361:Developmental and epileptic encephalopathy, 29;C5562044:Leukoencephalopathy, hereditary diffuse, with spheroids 2;C5562057:Trichothiodystrophy 8, nonphotosensitive (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.7
DANN	Benign	0.84
PhyloP100		1.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=93/7	polymorphism

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: rs117598688; hg19: chr16-70298949;