6-127813389-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001010923.3(THEMIS):ā€‹c.1252A>Gā€‹(p.Lys418Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

THEMIS
NM_001010923.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65
Variant links:
Genes affected
THEMIS (HGNC:21569): (thymocyte selection associated) This gene encodes a protein that plays a regulatory role in both positive and negative T-cell selection during late thymocyte development. The protein functions through T-cell antigen receptor signaling, and is necessary for proper lineage commitment and maturation of T-cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.073860615).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
THEMISNM_001010923.3 linkuse as main transcriptc.1252A>G p.Lys418Glu missense_variant 4/6 ENST00000368248.5 NP_001010923.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
THEMISENST00000368248.5 linkuse as main transcriptc.1252A>G p.Lys418Glu missense_variant 4/61 NM_001010923.3 ENSP00000357231 P1Q8N1K5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461462
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727032
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:
8.99e-7
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 18, 2021The c.1252A>G (p.K418E) alteration is located in exon 4 (coding exon 4) of the THEMIS gene. This alteration results from a A to G substitution at nucleotide position 1252, causing the lysine (K) at amino acid position 418 to be replaced by a glutamic acid (E). 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
0.078
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
19
DANN
Benign
0.78
DEOGEN2
Benign
0.042
T;T;.;T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.063
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.64
.;T;T;T;T
M_CAP
Benign
0.0059
T
MetaRNN
Benign
0.074
T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.6
L;L;.;.;L
MutationTaster
Benign
0.98
N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
0.86
.;N;N;.;.
REVEL
Benign
0.064
Sift
Benign
0.77
.;T;T;.;.
Sift4G
Benign
0.86
T;T;T;T;T
Polyphen
0.35
B;B;.;.;.
Vest4
0.14
MutPred
0.29
Loss of methylation at K418 (P = 0.0315);Loss of methylation at K418 (P = 0.0315);.;.;Loss of methylation at K418 (P = 0.0315);
MVP
0.12
ClinPred
0.17
T
GERP RS
5.7
Varity_R
0.085
gMVP
0.32

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: chr6-128134534; API