Variant 1-151895175-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_053055.5(THEM4):c.119A>G(p.Glu40Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,610,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

THEM4
NM_053055.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65

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:

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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 (MetaRNN=0.01715228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THEM4	NM_053055.5 linkuse as main transcript	c.119A>G	p.Glu40Gly	missense_variant	2/6	ENST00000368814.8	NP_444283.2	Q5T1C6A8K0C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
THEM4	ENST00000368814.8 linkuse as main transcript	c.119A>G	p.Glu40Gly	missense_variant	2/6	1	NM_053055.5	ENSP00000357804.3	Q5T1C6
THEM4	ENST00000471464.5 linkuse as main transcript	n.119A>G		non_coding_transcript_exon_variant	2/7	1		ENSP00000431288.1	F6XC58
THEM4	ENST00000489410.1 linkuse as main transcript	c.119A>G	p.Glu40Gly	missense_variant	2/2	2		ENSP00000433304.1	E9PLJ7
ENSG00000285651	ENST00000648930.1 linkuse as main transcript	n.32-1137T>C		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000894

AC:

AN:

246164

Hom.:

AF XY:

0.0000978

AC XY:

AN XY:

132914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00202

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1458030

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

725120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00169

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000494

AC:

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 submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.119A>G (p.E40G) alteration is located in exon 2 (coding exon 2) of the THEM4 gene. This alteration results from a A to G substitution at nucleotide position 119, causing the glutamic acid (E) at amino acid position 40 to be replaced by a glycine (G). 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

0.088

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.058

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.042

D;D

Polyphen

0.42

B;.

Vest4

0.24

MVP

0.14

MPC

0.15

ClinPred

0.068

GERP RS

3.9

Varity_R

0.13

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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