16-70265040-G-A

Variant names:

• chr16-70265040-G-A
• rs79785372
• NM_001605.3:c.1410C>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.1410C>T​(p.Ile470Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,614,120 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (3 hom.)
• Consequence: AARS1 NM_001605.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.560
• 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: 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=-0.51).
• BP6: Variant 16-70265040-G-A is Benign according to our data. Variant chr16-70265040-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 320342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000092 (14/152252) while in subpopulation EAS AF = 0.00174 (9/5178). AF 95% confidence interval is 0.000907. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.1410C>T	p.Ile470Ile	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.1410C>T	p.Ile470Ile	synonymous	Exon 11 of 21	ENSP00000261772.8	P49588-1
	AARS1	ENST00000565361.3	TSL:5	c.1410C>T	p.Ile470Ile	synonymous	Exon 11 of 22	ENSP00000455360.3	H3BPK7
	AARS1	ENST00000896288.1		c.1410C>T	p.Ile470Ile	synonymous	Exon 11 of 22	ENSP00000566347.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000402 AC: 101 AN: 251468 AF XY: 0.000390

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00386

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1461868 Hom.: 3 Cov.: 32 AF XY: 0.000175 AC XY: 127 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

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

East Asian (EAS) AF: 0.00232 AC: 92 AN: 39700

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112004

Other (OTH) AF: 0.000447 AC: 27 AN: 60392

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152252 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74436

African (AFR) AF: 0.0000241 AC: 1 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000215

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease axonal type 2N (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.0
DANN	Benign	0.83
PhyloP100		-0.56

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: rs79785372; hg19: chr16-70298943;