16-75628014-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005548.3(KARS1):c.1696-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,415,436 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (25 hom.)
• Consequence: KARS1 NM_005548.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.16

Genes affected

KARS1 (HGNC:6215): (lysyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-75628014-C-T is Benign according to our data. Variant chr16-75628014-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00352 (536/152274) while in subpopulation NFE AF= 0.00588 (400/68028). AF 95% confidence interval is 0.0054. There are 3 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KARS1	NM_005548.3	c.1696-21G>A		intron_variant		ENST00000302445.8
KARS1	NM_001130089.2	c.1780-21G>A		intron_variant
KARS1	NM_001378148.1	c.1228-21G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KARS1	ENST00000302445.8	c.1696-21G>A		intron_variant		1	NM_005548.3	A1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00281 AC: 701 AN: 249792 Hom.: 4 AF XY: 0.00285 AC XY: 385 AN XY: 135224

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00508 AC: 6420 AN: 1263162 Hom.: 25 Cov.: 18 AF XY: 0.00494 AC XY: 3159 AN XY: 639210

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00180

Gnomad4 ASJ exome AF: 0.000200

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.00652

Gnomad4 OTH exome AF: 0.00350

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152274 Hom.: 3 Cov.: 33 AF XY: 0.00330 AC XY: 246 AN XY: 74460

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00390

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 28, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.34
Dann	Benign	0.31

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: rs188921559; hg19: chr16-75661912;