16-75627869-G-C

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.*26C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,293,254 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (80 hom.)
• Consequence: KARS1 NM_005548.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.271

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=-0.83).
• BP6: Variant 16-75627869-G-C is Benign according to our data. Variant chr16-75627869-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 320623.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00761 (1159/152348) while in subpopulation NFE AF= 0.00917 (624/68040). AF 95% confidence interval is 0.00858. There are 15 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KARS1	NM_005548.3	c.*26C>G		3_prime_UTR_variant	14/14	ENST00000302445.8
KARS1	NM_001130089.2	c.*26C>G		3_prime_UTR_variant	15/15
KARS1	NM_001378148.1	c.*26C>G		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KARS1	ENST00000302445.8	c.*26C>G		3_prime_UTR_variant	14/14	1	NM_005548.3	A1

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 1159 AN: 152230 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00917

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00839 AC: 2109 AN: 251336 Hom.: 17 AF XY: 0.00845 AC XY: 1148 AN XY: 135868

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0337

Gnomad NFE exome AF: 0.00903

Gnomad OTH exome AF: 0.00913

GnomAD4 exome AF: 0.00896 AC: 10217 AN: 1140906 Hom.: 80 Cov.: 16 AF XY: 0.00872 AC XY: 5090 AN XY: 583448

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.0346

Gnomad4 NFE exome AF: 0.00880

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00761 AC: 1159 AN: 152348 Hom.: 15 Cov.: 33 AF XY: 0.00816 AC XY: 608 AN XY: 74498

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0337

Gnomad4 NFE AF: 0.00917

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00632 Hom.: 1

Bravo AF: 0.00526

Asia WGS AF: 0.00318 AC: 11 AN: 3478

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 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.7
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs78654839; hg19: chr16-75661767;