17-42951824-G-A

Variant names:

• chr17-42951824-G-A
• rs371979961
• NM_001261434.2:c.1079C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001261434.2(AARSD1):​c.1079C>T​(p.Ala360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,030 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AARSD1 NM_001261434.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

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: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]

ACMG classification

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=0.07009035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARSD1	NM_001261434.2	c.1079C>T	p.Ala360Val	missense_variant	Exon 11 of 12	ENST00000427569.7	NP_001248363.1
PTGES3L-AARSD1	NM_001136042.2	c.1601C>T	p.Ala534Val	missense_variant	Exon 16 of 17		NP_001129514.2
PTGES3L-AARSD1	NM_025267.4	c.1418C>T	p.Ala473Val	missense_variant	Exon 16 of 17		NP_079543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARSD1	ENST00000427569.7	c.1079C>T	p.Ala360Val	missense_variant	Exon 11 of 12	5	NM_001261434.2	ENSP00000400870.1
PTGES3L-AARSD1	ENST00000421990.7	c.1472C>T	p.Ala491Val	missense_variant	Exon 16 of 17	2		ENSP00000409924.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251348 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727234

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1601C>T (p.A534V) alteration is located in exon 16 (coding exon 16) of the AARSD1 gene. This alteration results from a C to T substitution at nucleotide position 1601, causing the alanine (A) at amino acid position 534 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	0.085
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0049	T;.;.;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.70	T;T;.;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.070	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.94	N;N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.082	T;T;T;T;T
Polyphen		0.0010	B;.;.;B;.
Vest4		0.21
MVP		0.088
MPC		0.11
ClinPred		0.086	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371979961; hg19: chr17-41103841;