Variant 17-42954924-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001261434.2(AARSD1):c.905A>G(p.His302Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

AARSD1
NM_001261434.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Variant links:

Genes affected

AARSD1 (HGNC:28417): (alanyl-tRNA synthetase domain containing 1) Predicted to enable Ser-tRNA(Ala) hydrolase activity. Predicted to be involved in regulation of translational fidelity. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

AARSD1 links:

PTGES3L-AARSD1 (HGNC:):

PTGES3L-AARSD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06757271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AARSD1	NM_001261434.2 linkuse as main transcript	c.905A>G	p.His302Arg	missense_variant	9/12	ENST00000427569.7
PTGES3L-AARSD1	NM_001136042.2 linkuse as main transcript	c.1427A>G	p.His476Arg	missense_variant	14/17
PTGES3L-AARSD1	NM_025267.4 linkuse as main transcript	c.1244A>G	p.His415Arg	missense_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARSD1	ENST00000427569.7 linkuse as main transcript	c.905A>G	p.His302Arg	missense_variant	9/12	5	NM_001261434.2	P1	Q9BTE6-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251486

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.1427A>G (p.H476R) alteration is located in exon 14 (coding exon 14) of the AARSD1 gene. This alteration results from a A to G substitution at nucleotide position 1427, causing the histidine (H) at amino acid position 476 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.67

Cadd

Benign

9.1

Dann

Benign

0.85

DEOGEN2

Benign

0.0011

T;.;.;T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.44

T;T;.;T;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.068

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.36

N;.;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

0.020

N;N;N;N;N

REVEL

Benign

0.0080

Sift

Benign

0.31

T;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T

Polyphen

0.0

B;.;.;B;.

Vest4

0.13

MutPred

0.36

.;.;.;Gain of MoRF binding (P = 0.0154);.;

MVP

0.055

MPC

0.14

ClinPred

0.028

GERP RS

1.7

Varity_R

0.022

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over