17-42956499-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001261434.2(AARSD1):c.451G>A(p.Val151Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: AARSD1 NM_001261434.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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]

PTGES3L-AARSD1 (HGNC:):

ACMG classification

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=0.054412216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARSD1	NM_001261434.2	c.451G>A	p.Val151Ile	missense_variant	5/12	ENST00000427569.7
PTGES3L-AARSD1	NM_001136042.2	c.973G>A	p.Val325Ile	missense_variant	10/17
PTGES3L-AARSD1	NM_025267.4	c.790G>A	p.Val264Ile	missense_variant	10/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARSD1	ENST00000427569.7	c.451G>A	p.Val151Ile	missense_variant	5/12	5	NM_001261434.2	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250904 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135642

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.973G>A (p.V325I) alteration is located in exon 10 (coding exon 10) of the AARSD1 gene. This alteration results from a G to A substitution at nucleotide position 973, causing the valine (V) at amino acid position 325 to be replaced by an isoleucine (I). 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	0.090
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0028	T;.;.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T;T;.;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.054	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.26	N;.;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.32	T;.;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;.
Vest4		0.081
MutPred		0.34		.;.;.;.;Loss of glycosylation at T230 (P = 0.1805);.;
MVP		0.12
MPC		0.090
ClinPred		0.19	T
GERP RS		4.3
Varity_R		0.051
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs913661176; hg19: chr17-41108516;