1-151889366-C-G

Position:

• chr1-151889366-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_053055.5(THEM4):​c.294G>C​(p.Lys98Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,612,862 control chromosomes in the GnomAD database, including 42 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 0.0090 (30 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (12 hom.)
• Consequence: THEM4 NM_053055.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.469

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035419464).
• BP6: Variant 1-151889366-C-G is Benign according to our data. Variant chr1-151889366-C-G is described in ClinVar as [Benign]. Clinvar id is 772815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00898 (1368/152268) while in subpopulation AFR AF= 0.0317 (1316/41536). AF 95% confidence interval is 0.0303. There are 30 homozygotes in gnomad4. There are 638 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THEM4	NM_053055.5	c.294G>C	p.Lys98Asn	missense_variant	3/6	ENST00000368814.8	NP_444283.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THEM4	ENST00000368814.8	c.294G>C	p.Lys98Asn	missense_variant	3/6	1	NM_053055.5	ENSP00000357804.3

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1363 AN: 152150 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00215 AC: 539 AN: 250472 Hom.: 6 AF XY: 0.00175 AC XY: 237 AN XY: 135430

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.000991

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000875 AC: 1278 AN: 1460594 Hom.: 12 Cov.: 30 AF XY: 0.000779 AC XY: 566 AN XY: 726628

Gnomad4 AFR exome AF: 0.0327

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00898 AC: 1368 AN: 152268 Hom.: 30 Cov.: 33 AF XY: 0.00857 AC XY: 638 AN XY: 74450

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00948

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00264 AC: 320

Asia WGS AF: 0.000866 AC: 4 AN: 3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.54
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.026
Sift	Benign	0.29	T
Sift4G	Benign	0.33	T
Polyphen		0.78	P
Vest4		0.34
MutPred		0.36		Loss of ubiquitination at K98 (P = 0.0092);
MVP		0.030
MPC		0.13
ClinPred		0.0083	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
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: rs73009658; hg19: chr1-151861842;