17-5489248-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001258217.2(MIS12):ā€‹c.386A>Cā€‹(p.Lys129Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

MIS12
NM_001258217.2 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18
Variant links:
Genes affected
MIS12 (HGNC:24967): (MIS12 kinetochore complex component) Involved in attachment of mitotic spindle microtubules to kinetochore and kinetochore assembly. Located in kinetochore and nucleus. Part of MIS12/MIND type 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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MIS12NM_001258217.2 linkuse as main transcriptc.386A>C p.Lys129Thr missense_variant 3/3 ENST00000611091.5 NP_001245146.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MIS12ENST00000611091.5 linkuse as main transcriptc.386A>C p.Lys129Thr missense_variant 3/32 NM_001258217.2 ENSP00000484532 P1
MIS12ENST00000381165.3 linkuse as main transcriptc.386A>C p.Lys129Thr missense_variant 3/31 ENSP00000370557 P1
MIS12ENST00000573759.1 linkuse as main transcriptc.386A>C p.Lys129Thr missense_variant 2/21 ENSP00000461252 P1
MIS12ENST00000576988.1 linkuse as main transcript downstream_gene_variant 4 ENSP00000461333

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461850
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727222
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:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 19, 2024The c.386A>C (p.K129T) alteration is located in exon 3 (coding exon 1) of the MIS12 gene. This alteration results from a A to C substitution at nucleotide position 386, causing the lysine (K) at amino acid position 129 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.037
T
BayesDel_noAF
Benign
-0.29
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;T;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.81
T;.;.
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.50
T;T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.5
M;M;M
MutationTaster
Benign
0.89
D;D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.4
.;.;D
REVEL
Benign
0.24
Sift
Uncertain
0.016
.;.;D
Sift4G
Uncertain
0.039
D;D;D
Polyphen
0.98
D;D;D
Vest4
0.30
MutPred
0.51
Loss of ubiquitination at K129 (P = 0.0041);Loss of ubiquitination at K129 (P = 0.0041);Loss of ubiquitination at K129 (P = 0.0041);
MVP
0.78
MPC
1.0
ClinPred
0.94
D
GERP RS
6.1
Varity_R
0.52
gMVP
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: chr17-5392568; API