rs148383122

chr16-70255792-G-Achr16-70255792-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001605.3(AARS1):c.2222C>T(p.Thr741Met) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T741K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24161422).
• BP6: Variant 16-70255792-G-A is Benign according to our data. Variant chr16-70255792-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246148.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000341 (52/152298) while in subpopulation AFR AF= 0.00077 (32/41572). AF 95% confidence interval is 0.000559. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS1	NM_001605.3	c.2222C>T	p.Thr741Met	missense_variant	16/21	ENST00000261772.13
AARS1	XM_047433666.1	c.2037C>T	p.Asp679=	synonymous_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS1	ENST00000261772.13	c.2222C>T	p.Thr741Met	missense_variant	16/21	1	NM_001605.3	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251308 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135856

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73 AN XY: 727224

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152298 Hom.: 1 Cov.: 31 AF XY: 0.000416 AC XY: 31 AN XY: 74466

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2023

Reported previously as a variant of uncertain significance in a patient with a suspected diagnosis of Charcot-Marie-Tooth disease (CMT); however, no further clinical or segregation information was provided (Volodarsky et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25817015, 32376792) -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.67	P
Vest4		0.48
MVP		0.81
MPC		0.55
ClinPred		0.094	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs148383122; hg19: chr16-70289695; COSMIC: COSV99933514; COSMIC: COSV99933514;