Variant chr1-151895070-C-T 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.224G>A(p.Arg75His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

THEM4
NM_053055.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.363

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=0.06012544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THEM4	NM_053055.5 linkuse as main transcript	c.224G>A	p.Arg75His	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.224G>A	p.Arg75His	missense_variant	2/6	1	NM_053055.5	ENSP00000357804.3	Q5T1C6
THEM4	ENST00000471464.5 linkuse as main transcript	n.224G>A		non_coding_transcript_exon_variant	2/7	1		ENSP00000431288.1	F6XC58
THEM4	ENST00000489410.1 linkuse as main transcript	c.224G>A	p.Arg75His	missense_variant	2/2	2		ENSP00000433304.1	E9PLJ7
ENSG00000285651	ENST00000648930.1 linkuse as main transcript	n.32-1242C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251414

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135874

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:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727236

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:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74258

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:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

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

Mar 02, 2023

The c.224G>A (p.R75H) 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 224, causing the arginine (R) at amino acid position 75 to be replaced by a histidine (H). 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

0.081

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.5

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

D;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.085

Sift

Benign

0.037

D;D

Sift4G

Uncertain

0.051

T;T

Polyphen

0.033

B;.

Vest4

0.19

MutPred

0.48

Gain of ubiquitination at K80 (P = 0.0444);Gain of ubiquitination at K80 (P = 0.0444);

MVP

0.014

MPC

0.13

ClinPred

0.070

GERP RS

-0.052

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.45

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

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