Genetic Variant NM_001159542.3:c.73G>A (chr8-127415939-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001159542.3(POU5F1B):c.73G>A(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,407,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

POU5F1B
NM_001159542.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0330

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03604403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1B	NM_001159542.3 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 1	ENST00000696633.1	NP_001153014.1	Q06416
POU5F1B	NM_001395745.1 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 2 of 2		NP_001382674.1
CASC8	NR_117100.1 link	n.1176+4890C>T		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 1		NM_001159542.3	ENSP00000512769.1		Q06416

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

165834

AF XY:

0.0000112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000355

AC:

AN:

1407936

Hom.:

Cov.:

113

AF XY:

0.00000144

AC XY:

AN XY:

695498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32218

American (AMR)

AF:

0.00

AC:

AN:

36672

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25088

East Asian (EAS)

AF:

0.00

AC:

AN:

36998

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4908

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084940

Other (OTH)

AF:

0.0000343

AC:

AN:

58238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000857

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.13

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.00063

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00069

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

N;N

PhyloP100

0.033

PrimateAI

Benign

0.47

PROVEAN

Benign

0.060

.;N

REVEL

Benign

0.081

Sift

Benign

0.21

.;T

Sift4G

Benign

0.40

.;T

Polyphen

0.049

B;B

Vest4

0.054

MutPred

0.063

Gain of phosphorylation at A25 (P = 0.048);Gain of phosphorylation at A25 (P = 0.048);

MVP

0.067

MPC

0.041

ClinPred

0.085

GERP RS

0.23

Varity_R

0.031

gMVP

0.16

Mutation Taster

=100/0

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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NM_001159542.3:c.73G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over