rs147319762

Variant names:

• chr16-70253980-T-C
• rs147319762
• NM_001605.3:c.2459A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001605.3(AARS1):​c.2459A>G​(p.Lys820Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,614,152 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K820N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.10
• Publications: 7 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 (MetaRNN=0.010879695).
• BP6: Variant 16-70253980-T-C is Benign according to our data. Variant chr16-70253980-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 220930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00179 (272/152262) while in subpopulation AMR AF = 0.00556 (85/15294). AF 95% confidence interval is 0.0046. There are 0 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.2459A>G	p.Lys820Arg	missense	Exon 18 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.2459A>G	p.Lys820Arg	missense	Exon 18 of 21	ENSP00000261772.8	P49588-1
	AARS1	ENST00000565361.3	TSL:5	c.2552A>G	p.Lys851Arg	missense	Exon 19 of 22	ENSP00000455360.3	H3BPK7
	AARS1	ENST00000896288.1		c.2552A>G	p.Lys851Arg	missense	Exon 19 of 22	ENSP00000566347.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00169 AC: 424 AN: 251452 AF XY: 0.00163

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00256 AC: 3736 AN: 1461890 Hom.: 9 Cov.: 33 AF XY: 0.00251 AC XY: 1823 AN XY: 727246

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00378 AC: 169 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86258

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53418

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.00297 AC: 3306 AN: 1112010

Other (OTH) AF: 0.00194 AC: 117 AN: 60396

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74448

African (AFR) AF: 0.000337 AC: 14 AN: 41548

American (AMR) AF: 0.00556 AC: 85 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00203 Hom.: 1

Bravo AF: 0.00193

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	1	AARS1-related disorder (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2N (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Benign	0.15	T
Sift4G	Benign	0.22	T
Polyphen		0.98	D
Vest4		0.38
MVP		0.80
MPC		0.13
ClinPred		0.044	T
GERP RS		5.5
Varity_R		0.40
gMVP		0.46
Mutation Taster		=51/49	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: rs147319762; hg19: chr16-70287883;