chr1-151889366-C-G

Variant names:

• chr1-151889366-C-G
• rs73009658
• NM_053055.5:c.294G>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THEM4	NM_053055.5	MANE Select	c.294G>C	p.Lys98Asn	missense	Exon 3 of 6	NP_444283.2	Q5T1C6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THEM4	ENST00000368814.8	TSL:1 MANE Select	c.294G>C	p.Lys98Asn	missense	Exon 3 of 6	ENSP00000357804.3	Q5T1C6
	THEM4	ENST00000471464.5	TSL:1	n.*202G>C		non_coding_transcript_exon	Exon 4 of 7	ENSP00000431288.1	F6XC58
	THEM4	ENST00000471464.5	TSL:1	n.*202G>C		3_prime_UTR	Exon 4 of 7	ENSP00000431288.1	F6XC58

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

GnomAD2 exomes AF: 0.00215 AC: 539 AN: 250472 AF XY: 0.00175

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 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

African (AFR) AF: 0.0327 AC: 1092 AN: 33374

American (AMR) AF: 0.00110 AC: 49 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111410

Other (OTH) AF: 0.00171 AC: 103 AN: 60326

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

African (AFR) AF: 0.0317 AC: 1316 AN: 41536

American (AMR) AF: 0.00209 AC: 32 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.47
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs73009658; hg19: chr1-151861842;