chr16-70252896-T-C

Variant names:

• chr16-70252896-T-C
• rs746822330
• NM_001605.3:c.2732A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001605.3(AARS1):​c.2732A>G​(p.Asn911Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 2.22
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049456924).
• BP6: Variant 16-70252896-T-C is Benign according to our data. Variant chr16-70252896-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 320324.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AARS1	NM_001605.3	MANE Select	c.2732A>G	p.Asn911Ser	missense	Exon 21 of 21	NP_001596.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AARS1	ENST00000261772.13	TSL:1 MANE Select	c.2732A>G	p.Asn911Ser	missense	Exon 21 of 21	ENSP00000261772.8
	AARS1	ENST00000565361.3	TSL:5	c.2825A>G	p.Asn942Ser	missense	Exon 22 of 22	ENSP00000455360.3
	AARS1	ENST00000896288.1		c.2825A>G	p.Asn942Ser	missense	Exon 22 of 22	ENSP00000566347.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 250788 AF XY: 0.000103

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111994

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152062 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74250

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	AARS1-related disorder (1)
-	1	-	Charcot-Marie-Tooth disease (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	0.054
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.52	N
PhyloP100		2.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.74
MPC		0.12
ClinPred		0.030	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.16
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746822330; hg19: chr16-70286799;