Genetic Variant THEM4:p.Arg81His (chr1-151895052-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_053055.5(THEM4):c.242G>A(p.Arg81His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00931 in 1,613,964 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 75 hom. )

Consequence

THEM4
NM_053055.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.89

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033552647).

BP6

Variant 1-151895052-C-T is Benign according to our data. Variant chr1-151895052-C-T is described in ClinVar as [Benign]. Clinvar id is 770328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEM4	NM_053055.5 link	c.242G>A	p.Arg81His	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.242G>A	p.Arg81His	missense_variant	Exon 2 of 6	1	NM_053055.5	ENSP00000357804.3	Q5T1C6
THEM4	ENST00000471464.5 link	n.242G>A		non_coding_transcript_exon_variant	Exon 2 of 7	1		ENSP00000431288.1	F6XC58
THEM4	ENST00000489410.1 link	c.242G>A	p.Arg81His	missense_variant	Exon 2 of 2	2		ENSP00000433304.1	E9PLJ7
ENSG00000285651	ENST00000648930.1 link	n.32-1260C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

1017

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00748

AC:

1881

AN:

251390

Hom.:

AF XY:

0.00735

AC XY:

999

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00959

AC:

14014

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00924

AC XY:

6716

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.0164

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00684

GnomAD4 genome

AF:

0.00668

AC:

1017

AN:

152132

Hom.:

Cov.:

AF XY:

0.00671

AC XY:

499

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00157

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0168

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00927

Hom.:

Bravo

AF:

0.00510

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00953

AC:

ExAC

AF:

0.00798

AC:

969

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00900

EpiControl

AF:

0.00741

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0080

DANN

Benign

0.73

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.35

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.021

Sift

Benign

0.47

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.35

B;.

Vest4

0.069

MVP

0.014

MPC

0.098

ClinPred

0.0070

GERP RS

-6.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.35

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