chr17-42951854-C-G

Variant names:

• chr17-42951854-C-G
• rs144615663
• NM_001261434.2:c.1049G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001261434.2(AARSD1):​c.1049G>C​(p.Gly350Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000367 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G350V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: AARSD1 NM_001261434.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.69
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01557678).
• BP6: Variant 17-42951854-C-G is Benign according to our data. Variant chr17-42951854-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3139403.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARSD1	NM_001261434.2	c.1049G>C	p.Gly350Ala	missense_variant	Exon 11 of 12	ENST00000427569.7	NP_001248363.1
PTGES3L-AARSD1	NM_001136042.2	c.1571G>C	p.Gly524Ala	missense_variant	Exon 16 of 17		NP_001129514.2
PTGES3L-AARSD1	NM_025267.4	c.1388G>C	p.Gly463Ala	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.1049G>C	p.Gly350Ala	missense_variant	Exon 11 of 12	5	NM_001261434.2	ENSP00000400870.1
PTGES3L-AARSD1	ENST00000421990.7	c.1442G>C	p.Gly481Ala	missense_variant	Exon 16 of 17	2		ENSP00000409924.2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000266 AC: 67 AN: 251408 AF XY: 0.000243

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000380 AC: 555 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.000374 AC XY: 272 AN XY: 727240

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

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

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53396

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

European-Non Finnish (NFE) AF: 0.000458 AC: 509 AN: 1112012

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74474

African (AFR) AF: 0.0000481 AC: 2 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 17, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.38
DEOGEN2	Benign	0.00094	T;.;.;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.14	T;T;.;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N;.;.;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	1.8	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;.;.;B;.
Vest4		0.17
MVP		0.16
MPC		0.12
ClinPred		0.039	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.058
gMVP		0.44
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs144615663; hg19: chr17-41103871;