Genetic Variant POU5F1B:p.Glu56Asp (chr8-127416034-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001159542.3(POU5F1B):c.168G>T(p.Glu56Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

POU5F1B
NM_001159542.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.114

Publications

0 publications found

Variant links:

Genes affected

POU5F1B (HGNC:9223): (POU class 5 homeobox 1B) This intronless gene was thought to be a transcribed pseudogene of POU class 5 homeobox 1, however, it has been reported that this gene can encode a functional protein. The encoded protein is nearly the same length as and highly similar to the POU class 5 homeobox 1 transcription factor, has been shown to be a weak transcriptional activator and may play a role in carcinogenesis and eye development. [provided by RefSeq, Apr 2009]

POU5F1B links:

CASC8 (HGNC:45129): (cancer susceptibility 8)

CASC8 links:

PCAT1 (HGNC:43022): (prostate cancer associated transcript 1) This gene produces a long non-coding RNA that promotes cell proliferation and is upregulated in prostate, colorectal, and other cancers. This RNA negatively regulates the BRCA2 tumor suppressor protein and positively regulates Myc oncoprotein. It contains binding sites for microRNAs, and may act as a sponge for microRNAs that regulate cell growth pathways. [provided by RefSeq, Dec 2017]

PCAT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074273765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1B	NM_001159542.3 link	c.168G>T	p.Glu56Asp	missense_variant	Exon 1 of 1	ENST00000696633.1	NP_001153014.1	Q06416
POU5F1B	NM_001395745.1 link	c.168G>T	p.Glu56Asp	missense_variant	Exon 2 of 2		NP_001382674.1
CASC8	NR_117100.1 link	n.1176+4795C>A		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1 link	c.168G>T	p.Glu56Asp	missense_variant	Exon 1 of 1		NM_001159542.3	ENSP00000512769.1		Q06416

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453342

Hom.:

Cov.:

114

AF XY:

0.00

AC XY:

AN XY:

722348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33234

American (AMR)

AF:

0.00

AC:

AN:

44108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25930

East Asian (EAS)

AF:

0.00

AC:

AN:

39304

South Asian (SAS)

AF:

0.00

AC:

AN:

84966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5412

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108624

Other (OTH)

AF:

0.00

AC:

AN:

60016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.168G>T (p.E56D) alteration is located in exon 1 (coding exon 1) of the POU5F1B gene. This alteration results from a G to T substitution at nucleotide position 168, causing the glutamic acid (E) at amino acid position 56 to be replaced by an aspartic acid (D). 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

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

2.6

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0033

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.074

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

L;L

PhyloP100

-0.11

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.65

.;N

REVEL

Benign

0.069

Sift

Benign

0.12

.;T

Sift4G

Benign

0.51

.;T

Polyphen

0.011

B;B

Vest4

0.093

MutPred

0.15

Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);

MVP

0.19

MPC

0.043

ClinPred

0.062

GERP RS

0.86

Varity_R

0.082

gMVP

0.31

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over