dbSNP rs374675852: KARS1:c.-1G>T (chr16-75647640-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005548.3(KARS1):c.-1G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,842 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

KARS1
NM_005548.3 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.913

Variant links:

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]

KARS1 links:

TERF2IP (HGNC:19246): (TERF2 interacting protein) Enables G-rich strand telomeric DNA binding activity and phosphatase binding activity. Involved in several processes, including positive regulation of NIK/NF-kappaB signaling; regulation of nucleobase-containing compound metabolic process; and regulation of protein modification process. Located in chromosome, telomeric region; cytosol; and nuclear body. Part of shelterin complex. [provided by Alliance of Genome Resources, Apr 2022]

TERF2IP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3 link	c.-1G>T		5_prime_UTR_variant	Exon 1 of 14	ENST00000302445.8	NP_005539.1	Q15046-1
TERF2IP	NM_018975.4 link	c.-243C>A		upstream_gene_variant		ENST00000300086.5	NP_061848.2	Q9NYB0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 link	c.-1G>T		5_prime_UTR_variant	Exon 1 of 14	1	NM_005548.3	ENSP00000303043.3		Q15046-1
TERF2IP	ENST00000300086.5 link	c.-243C>A		upstream_gene_variant		1	NM_018975.4	ENSP00000300086.4		Q9NYB0

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000249

AC:

AN:

249378

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

135288

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.000842

Gnomad ASJ exome

AF:

0.00190

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.000823

GnomAD4 exome

AF:

0.000121

AC:

177

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000140

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-1G>T variant in KARS has not been previously reported in individuals with hearing loss, but has been identified in 12/61810 of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs37 4675852). This variant is located in the 5' UTR and its impact is unclear. In su mmary, the clinical significance of the c.-1G>T variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over