17-42953740-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001261434.2(AARSD1):c.992A>G(p.Asn331Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

AARSD1
NM_001261434.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.202063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARSD1	NM_001261434.2 link	c.992A>G	p.Asn331Ser	missense_variant	Exon 10 of 12	ENST00000427569.7	NP_001248363.1	Q9BTE6-1
PTGES3L-AARSD1	NM_001136042.2 link	c.1514A>G	p.Asn505Ser	missense_variant	Exon 15 of 17		NP_001129514.2	Q9BTE6-3
PTGES3L-AARSD1	NM_025267.4 link	c.1331A>G	p.Asn444Ser	missense_variant	Exon 15 of 17		NP_079543.1	Q9BTE6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARSD1	ENST00000427569.7 link	c.992A>G	p.Asn331Ser	missense_variant	Exon 10 of 12	5	NM_001261434.2	ENSP00000400870.1		Q9BTE6-1
PTGES3L-AARSD1	ENST00000421990.7 link	c.1385A>G	p.Asn462Ser	missense_variant	Exon 15 of 17	2		ENSP00000409924.2		B3KSP9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

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:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251488

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1514A>G (p.N505S) alteration is located in exon 15 (coding exon 15) of the AARSD1 gene. This alteration results from a A to G substitution at nucleotide position 1514, causing the asparagine (N) at amino acid position 505 to be replaced by a serine (S). 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

0.094

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;.;.;T;.

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D;.;D;D

M_CAP

Benign

0.0076

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.8

L;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.2

N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.30

T;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.0030

B;.;.;B;.

Vest4

0.46

MutPred

0.36

.;.;.;Gain of glycosylation at N414 (P = 0.0879);.;

MVP

0.24

MPC

0.090

ClinPred

0.15

GERP RS

5.4

Varity_R

0.13

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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