chr17-42954943-G-C

Position:

chr17-42954943-G-C

Variant summary

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

The NM_001261434.2(AARSD1):c.886C>G(p.Leu296Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,100 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 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

AARSD1
NM_001261434.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

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:43946): (PTGES3L-AARSD1 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring PTGES3L (prostaglandin E synthase 3 (cytosolic)-like) and AARSD1(alanyl-tRNA synthetase domain containing 1) genes on chromosome 17. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, May 2012]

PTGES3L-AARSD1 links:

AARSD1 (HGNC:):

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=0.05717385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AARSD1	NM_001261434.2 linkuse as main transcript	c.886C>G	p.Leu296Val	missense_variant	9/12	ENST00000427569.7	NP_001248363.1	Q9BTE6-1
PTGES3L-AARSD1	NM_001136042.2 linkuse as main transcript	c.1408C>G	p.Leu470Val	missense_variant	14/17		NP_001129514.2	Q9BTE6-3
PTGES3L-AARSD1	NM_025267.4 linkuse as main transcript	c.1225C>G	p.Leu409Val	missense_variant	14/17		NP_079543.1	Q9BTE6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AARSD1	ENST00000427569.7 linkuse as main transcript	c.886C>G	p.Leu296Val	missense_variant	9/12	5	NM_001261434.2	ENSP00000400870.1		Q9BTE6-1
PTGES3L-AARSD1	ENST00000421990.7 linkuse as main transcript	c.1279C>G	p.Leu427Val	missense_variant	14/17	2		ENSP00000409924.2		B3KSP9

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251482

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0000447

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000177

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000626

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:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000174

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

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

Jun 21, 2023

The c.1408C>G (p.L470V) alteration is located in exon 14 (coding exon 14) of the AARSD1 gene. This alteration results from a C to G substitution at nucleotide position 1408, causing the leucine (L) at amino acid position 470 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

T;.;.;T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

D;D;.;D;D

M_CAP

Benign

0.0069

MetaRNN

Benign

0.057

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

L;.;.;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

N;N;N;N;N

REVEL

Benign

0.043

Sift

Benign

0.20

T;T;T;T;T

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.17

B;.;.;B;.

Vest4

0.20

MVP

0.22

MPC

0.15

ClinPred

0.047

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.048

gMVP

0.64

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

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