NM_002161.6:c.3136G>A

Variant names:

• chr9-92242195-C-T
• rs34737051
• NM_002161.6:c.3136G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002161.6(IARS1):​c.3136G>A​(p.Val1046Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0066 in 1,614,020 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (43 hom.)
• Consequence: IARS1 NM_002161.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.72
• Publications: 7 publications found

Genes affected

IARS1 (HGNC:5330): (isoleucyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Isoleucine-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family and has been identified as a target of autoantibodies in the autoimmune disease polymyositis/dermatomyositis. Alternatively spliced transcript variants have been found. [provided by RefSeq, Nov 2012]

IARS1 Gene-Disease associations (from GenCC):

• growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070349574).
• BP6: Variant 9-92242195-C-T is Benign according to our data. Variant chr9-92242195-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00454 (692/152308) while in subpopulation NFE AF = 0.00807 (549/68016). AF 95% confidence interval is 0.00751. There are 2 homozygotes in GnomAd4. There are 308 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002161.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS1	NM_002161.6	MANE Select	c.3136G>A	p.Val1046Ile	missense	Exon 29 of 34	NP_002152.2	P41252
	IARS1	NM_001378569.1		c.3199G>A	p.Val1067Ile	missense	Exon 29 of 34	NP_001365498.1
	IARS1	NM_001378571.1		c.3157G>A	p.Val1053Ile	missense	Exon 29 of 34	NP_001365500.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS1	ENST00000443024.7	TSL:5 MANE Select	c.3136G>A	p.Val1046Ile	missense	Exon 29 of 34	ENSP00000406448.4	P41252
	IARS1	ENST00000375643.7	TSL:1	c.3136G>A	p.Val1046Ile	missense	Exon 29 of 34	ENSP00000364794.3	P41252
	IARS1	ENST00000447699.7	TSL:1	n.3136G>A		non_coding_transcript_exon	Exon 29 of 35	ENSP00000415020.3	J3KR24

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152190 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00807

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00468 AC: 1176 AN: 251292 AF XY: 0.00466

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00845

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00681 AC: 9959 AN: 1461712 Hom.: 43 Cov.: 31 AF XY: 0.00680 AC XY: 4942 AN XY: 727160

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00157 AC: 135 AN: 86244

European-Finnish (FIN) AF: 0.00247 AC: 132 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00824 AC: 9165 AN: 1111888

Other (OTH) AF: 0.00548 AC: 331 AN: 60392

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152308 Hom.: 2 Cov.: 33 AF XY: 0.00413 AC XY: 308 AN XY: 74492

African (AFR) AF: 0.00130 AC: 54 AN: 41566

American (AMR) AF: 0.00261 AC: 40 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00807 AC: 549 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00672 Hom.: 6

Bravo AF: 0.00435

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00502 AC: 610

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00658

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	IARS1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.069	T
Eigen	Benign	0.025
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.099
Sift	Benign	0.19	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.31
MVP		0.53
MPC		0.080
ClinPred		0.015	T
GERP RS		6.0
Varity_R		0.059
gMVP		0.40
Mutation Taster		=97/3	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: rs34737051; hg19: chr9-95004477; COSMIC: COSV65113219;