1-151895161-C-T

Variant names:

Variant summary

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

The NM_053055.5(THEM4):c.133G>A(p.Asp45Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

THEM4
NM_053055.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

THEM4 (HGNC:17947): (thioesterase superfamily member 4) Protein kinase B (PKB) is a major downstream target of receptor tyrosine kinases that signal via phosphatidylinositol 3-kinase. Upon cell stimulation, PKB is translocated to the plasma membrane, where it is phosphorylated in the C-terminal regulatory domain. The protein encoded by this gene negatively regulates PKB activity by inhibiting phosphorylation. Transcription of this gene is commonly downregulated in glioblastomas. [provided by RefSeq, Jul 2008]

THEM4 links:

ENSG00000285651 (HGNC:):

ENSG00000285651 links:

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=0.18064055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEM4	NM_053055.5 link	c.133G>A	p.Asp45Asn	missense_variant	Exon 2 of 6	ENST00000368814.8	NP_444283.2	Q5T1C6A8K0C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THEM4	ENST00000368814.8 link	c.133G>A	p.Asp45Asn	missense_variant	Exon 2 of 6	1	NM_053055.5	ENSP00000357804.3	Q5T1C6
THEM4	ENST00000471464.5 link	n.133G>A		non_coding_transcript_exon_variant	Exon 2 of 7	1		ENSP00000431288.1	F6XC58
THEM4	ENST00000489410.1 link	c.133G>A	p.Asp45Asn	missense_variant	Exon 2 of 2	2		ENSP00000433304.1	E9PLJ7
ENSG00000285651	ENST00000648930.1 link	n.32-1151C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152078

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249428

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460276

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726354

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133G>A (p.D45N) alteration is located in exon 2 (coding exon 2) of the THEM4 gene. This alteration results from a G to A substitution at nucleotide position 133, causing the aspartic acid (D) at amino acid position 45 to be replaced by an asparagine (N). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

D;D

REVEL

Benign

0.091

Sift

Benign

0.044

D;D

Sift4G

Benign

0.071

T;D

Polyphen

0.82

P;.

Vest4

0.44

MutPred

0.38

Gain of methylation at K44 (P = 0.0937);Gain of methylation at K44 (P = 0.0937);

MVP

0.095

MPC

0.26

ClinPred

0.83

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.36

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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