9-92293147-A-T

Variant names:

• chr9-92293147-A-T
• rs10820966
• NM_002161.6:c.-8+464T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002161.6(IARS1):​c.-8+464T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 152,092 control chromosomes in the GnomAD database, including 14,898 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (14898 hom., cov: 32)
• Consequence: IARS1 NM_002161.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• Publications: 4 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS1	NM_002161.6	MANE Select	c.-8+464T>A		intron	N/A	NP_002152.2
	IARS1	NM_001378569.1		c.-8+294T>A		intron	N/A	NP_001365498.1
	IARS1	NM_001378571.1		c.-8+464T>A		intron	N/A	NP_001365500.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS1	ENST00000443024.7	TSL:5 MANE Select	c.-8+464T>A		intron	N/A	ENSP00000406448.4
	IARS1	ENST00000375643.7	TSL:1	c.-8+294T>A		intron	N/A	ENSP00000364794.3
	IARS1	ENST00000447699.7	TSL:1	n.-8+464T>A		intron	N/A	ENSP00000415020.3

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61978 AN: 151974 Hom.: 14882 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.393

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.408 AC: 62032 AN: 152092 Hom.: 14898 Cov.: 32 AF XY: 0.398 AC XY: 29608 AN XY: 74320

African (AFR) AF: 0.665 AC: 27578 AN: 41486

American (AMR) AF: 0.295 AC: 4513 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1314 AN: 3468

East Asian (EAS) AF: 0.108 AC: 557 AN: 5168

South Asian (SAS) AF: 0.221 AC: 1068 AN: 4824

European-Finnish (FIN) AF: 0.278 AC: 2935 AN: 10572

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22605 AN: 67970

Other (OTH) AF: 0.387 AC: 819 AN: 2116

Alfa AF: 0.378 Hom.: 1615

Bravo AF: 0.423

Asia WGS AF: 0.181 AC: 627 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.9
DANN	Benign	0.78
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs10820966; hg19: chr9-95055429;