17-42950685-G-A

Variant names:

• chr17-42950685-G-A
• rs768300495
• NM_001261434.2:c.1147C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001261434.2(AARSD1):​c.1147C>T​(p.Arg383Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,613,760 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: AARSD1 NM_001261434.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34305155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARSD1	NM_001261434.2	c.1147C>T	p.Arg383Cys	missense_variant	Exon 12 of 12	ENST00000427569.7	NP_001248363.1
PTGES3L-AARSD1	NM_001136042.2	c.1669C>T	p.Arg557Cys	missense_variant	Exon 17 of 17		NP_001129514.2
PTGES3L-AARSD1	NM_025267.4	c.1486C>T	p.Arg496Cys	missense_variant	Exon 17 of 17		NP_079543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARSD1	ENST00000427569.7	c.1147C>T	p.Arg383Cys	missense_variant	Exon 12 of 12	5	NM_001261434.2	ENSP00000400870.1
PTGES3L-AARSD1	ENST00000421990.7	c.1540C>T	p.Arg514Cys	missense_variant	Exon 17 of 17	2		ENSP00000409924.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251222 AF XY: 0.00

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727170

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111970

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74224

African (AFR) AF: 0.0000967 AC: 4 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000354 Hom.: 0

Bravo AF: 0.0000113

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

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1669C>T (p.R557C) alteration is located in exon 17 (coding exon 17) of the AARSD1 gene. This alteration results from a C to T substitution at nucleotide position 1669, causing the arginine (R) at amino acid position 557 to be replaced by a cysteine (C). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.
PhyloP100		6.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.024	D;D;D;D;D
Sift4G	Uncertain	0.028	D;T;T;T;T
Polyphen		0.29	B;.;.;B;.
Vest4		0.52
MVP		0.41
MPC		0.18
ClinPred		0.87	D
GERP RS		4.9
Varity_R		0.34
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768300495; hg19: chr17-41102702;