1-151895052-C-T

Position:

• chr1-151895052-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.89

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]

ENSG00000285651 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
THEM4	NM_053055.5	c.242G>A	p.Arg81His	missense_variant	2/6	ENST00000368814.8	NP_444283.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THEM4	ENST00000368814.8	c.242G>A	p.Arg81His	missense_variant	2/6	1	NM_053055.5	ENSP00000357804.3
THEM4	ENST00000471464.5	n.242G>A		non_coding_transcript_exon_variant	2/7	1		ENSP00000431288.1
THEM4	ENST00000489410.1	c.242G>A	p.Arg81His	missense_variant	2/2	2		ENSP00000433304.1
ENSG00000285651	ENST00000648930.1	n.32-1260C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 1017 AN: 152014 Hom.: 6 Cov.: 32

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.: 18 AF XY: 0.00735 AC XY: 999 AN XY: 135874

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.: 75 Cov.: 29 AF XY: 0.00924 AC XY: 6716 AN XY: 727212

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.: 6 Cov.: 32 AF XY: 0.00671 AC XY: 499 AN XY: 74384

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.: 8

Bravo AF: 0.00510

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00798 AC: 969

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00741

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.65	T
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	N
LIST_S2	Benign	0.35	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

dbSNP: rs114800758; hg19: chr1-151867528; COSMIC: COSV64295580; COSMIC: COSV64295580;