Variant chr8-127416423-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001159542.3(POU5F1B):c.557G>C(p.Arg186Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POU5F1B
NM_001159542.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.36

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:):

CASC8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU5F1B	NM_001159542.3 linkuse as main transcript	c.557G>C	p.Arg186Pro	missense_variant	1/1	ENST00000696633.1	NP_001153014.1	Q06416
POU5F1B	NM_001395745.1 linkuse as main transcript	c.557G>C	p.Arg186Pro	missense_variant	2/2		NP_001382674.1
CASC8	NR_117100.1 linkuse as main transcript	n.1176+4406C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1 linkuse as main transcript	c.557G>C	p.Arg186Pro	missense_variant	1/1		NM_001159542.3	ENSP00000512769.1		Q06416

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455760

Hom.:

Cov.:

111

AF XY:

0.00

AC XY:

AN XY:

723358

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.557G>C (p.R186P) alteration is located in exon 1 (coding exon 1) of the POU5F1B gene. This alteration results from a G to C substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a proline (P). 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

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.76

D;D

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

.;D

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.5

L;L

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.7

.;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0010

.;D

Polyphen

0.050

B;B

Vest4

0.69

MutPred

0.83

Loss of MoRF binding (P = 0.0392);Loss of MoRF binding (P = 0.0392);

MVP

0.44

MPC

0.064

ClinPred

0.99

GERP RS

1.1

Varity_R

0.95

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over