16-75647635-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005548.3(KARS1):​c.5C>G​(p.Ala2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

1
10
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KARS1NM_005548.3 linkc.5C>G p.Ala2Gly missense_variant Exon 1 of 14 ENST00000302445.8 NP_005539.1 Q15046-1
TERF2IPNM_018975.4 linkc.-248G>C upstream_gene_variant ENST00000300086.5 NP_061848.2 Q9NYB0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KARS1ENST00000302445.8 linkc.5C>G p.Ala2Gly missense_variant Exon 1 of 14 1 NM_005548.3 ENSP00000303043.3 Q15046-1
TERF2IPENST00000300086.5 linkc.-248G>C upstream_gene_variant 1 NM_018975.4 ENSP00000300086.4 Q9NYB0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461430
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727036
show subpopulations
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:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.44
T
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.78
D
MetaSVM
Uncertain
0.17
D
MutationAssessor
Benign
1.7
L
PROVEAN
Benign
-0.33
N
REVEL
Uncertain
0.35
Sift
Uncertain
0.020
D
Sift4G
Uncertain
0.024
D
Polyphen
1.0
D
Vest4
0.61
MutPred
0.26
Loss of helix (P = 0.0123);
MVP
0.90
ClinPred
0.83
D
GERP RS
5.7
Varity_R
0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-75681533; API