chr17-42953770-C-A

Variant names:

• chr17-42953770-C-A
• rs150835196
• NM_001261434.2:c.962G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001261434.2(AARSD1):​c.962G>T​(p.Gly321Val) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: AARSD1 NM_001261434.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARSD1	NM_001261434.2	c.962G>T	p.Gly321Val	missense_variant	Exon 10 of 12	ENST00000427569.7	NP_001248363.1
PTGES3L-AARSD1	NM_001136042.2	c.1484G>T	p.Gly495Val	missense_variant	Exon 15 of 17		NP_001129514.2
PTGES3L-AARSD1	NM_025267.4	c.1301G>T	p.Gly434Val	missense_variant	Exon 15 of 17		NP_079543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARSD1	ENST00000427569.7	c.962G>T	p.Gly321Val	missense_variant	Exon 10 of 12	5	NM_001261434.2	ENSP00000400870.1
PTGES3L-AARSD1	ENST00000421990.7	c.1355G>T	p.Gly452Val	missense_variant	Exon 15 of 17	2		ENSP00000409924.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251484 AF XY: 0.0000515

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1461848 Hom.: 0 Cov.: 30 AF XY: 0.000127 AC XY: 92 AN XY: 727222

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1111980

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1484G>T (p.G495V) alteration is located in exon 15 (coding exon 15) of the AARSD1 gene. This alteration results from a G to T substitution at nucleotide position 1484, causing the glycine (G) at amino acid position 495 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	Pathogenic	0.82
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T;.;.;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	D;T;T;T;T
Sift4G	Benign	0.087	T;T;T;T;T
Polyphen		0.21	B;.;.;P;.
Vest4		0.81
MVP		0.43
MPC		0.24
ClinPred		0.78	D
GERP RS		4.3
Varity_R		0.75
gMVP		0.86
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs150835196; hg19: chr17-41105787;