chr1-151909364-T-A

Variant names:

• chr1-151909364-T-A
• NM_053055.5:c.95A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053055.5(THEM4):​c.95A>T​(p.Glu32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,359,488 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: THEM4 NM_053055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.689

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]

ACMG classification

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=0.04530886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEM4	NM_053055.5	c.95A>T	p.Glu32Val	missense_variant	Exon 1 of 6	ENST00000368814.8	NP_444283.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THEM4	ENST00000368814.8	c.95A>T	p.Glu32Val	missense_variant	Exon 1 of 6	1	NM_053055.5	ENSP00000357804.3
THEM4	ENST00000471464.5	n.95A>T		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000431288.1
THEM4	ENST00000489410.1	c.95A>T	p.Glu32Val	missense_variant	Exon 1 of 2	2		ENSP00000433304.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1359488 Hom.: 0 Cov.: 29 AF XY: 0.00000298 AC XY: 2 AN XY: 670838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000941

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95A>T (p.E32V) alteration is located in exon 1 (coding exon 1) of the THEM4 gene. This alteration results from a A to T substitution at nucleotide position 95, causing the glutamic acid (E) at amino acid position 32 to be replaced by a valine (V). 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	0.091
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.53
DANN	Benign	0.72
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00046	N
LIST_S2	Benign	0.13	T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.95	N;N
REVEL	Benign	0.010
Sift	Benign	0.36	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0	B;.
Vest4		0.087
MutPred		0.18		Loss of solvent accessibility (P = 0.0062);Loss of solvent accessibility (P = 0.0062);
MVP		0.030
MPC		0.088
ClinPred		0.064	T
GERP RS		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.058
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-151881840;