rs886037873

chr9-92223378-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_002161.6(IARS1):c.3521T>A(p.Ile1174Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IARS1 NM_002161.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 9-92223378-A-T is Pathogenic according to our data. Variant chr9-92223378-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 253318.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-92223378-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IARS1	NM_002161.6	c.3521T>A	p.Ile1174Asn	missense_variant	32/34	ENST00000443024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IARS1	ENST00000443024.7	c.3521T>A	p.Ile1174Asn	missense_variant	32/34	5	NM_002161.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251406 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135874

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: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461560 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727096

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: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.13	B;.;.
Vest4		0.92
MutPred		0.61		Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);.;
MVP		0.59
MPC		0.29
ClinPred		0.79	D
GERP RS		5.9
Varity_R		0.32
gMVP		0.82

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: rs886037873; hg19: chr9-94985660;