Genetic Variant POU5F1:p.Pro22Leu (chr6-31170556-G-A) – 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_002701.6(POU5F1):c.65C>T(p.Pro22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POU5F1
NM_002701.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.28

Publications

0 publications found

Variant links:

Genes affected

POU5F1 (HGNC:9221): (POU class 5 homeobox 1) This gene encodes a transcription factor containing a POU homeodomain that plays a key role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. This gene can participate in a translocation with the Ewing's sarcoma gene on chromosome 21, which also leads to tumor formation. Alternative splicing, as well as usage of alternative AUG and non-AUG translation initiation codons, results in multiple isoforms. One of the AUG start codons is polymorphic in human populations. Related pseudogenes have been identified on chromosomes 1, 3, 8, 10, and 12. [provided by RefSeq, Oct 2013]

POU5F1 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=0.14919311).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1	NM_002701.6 link	c.65C>T	p.Pro22Leu	missense_variant	Exon 1 of 5	ENST00000259915.13	NP_002692.2	Q01860-1D2IYK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POU5F1	ENST00000259915.13 link	c.65C>T	p.Pro22Leu	missense_variant	Exon 1 of 5	1	NM_002701.6	ENSP00000259915.7	Q01860-1
POU5F1	ENST00000461401.1 link	n.103C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
POU5F1	ENST00000441888.7 link	c.-183-4509C>T		intron_variant	Intron 1 of 4	1		ENSP00000389359.2	F2Z381

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701404

African (AFR)

AF:

0.00

AC:

AN:

32492

American (AMR)

AF:

0.00

AC:

AN:

38038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25282

East Asian (EAS)

AF:

0.00

AC:

AN:

37444

South Asian (SAS)

AF:

0.00

AC:

AN:

81062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090486

Other (OTH)

AF:

0.00

AC:

AN:

58690

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

Mar 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.65C>T (p.P22L) alteration is located in exon 1 (coding exon 1) of the POU5F1 gene. This alteration results from a C to T substitution at nucleotide position 65, causing the proline (P) at amino acid position 22 to be replaced by a leucine (L). 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

0.086

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.73

M_CAP

Benign

0.069

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

PhyloP100

1.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.078

Sift

Benign

0.14

T;.

Sift4G

Benign

0.58

T;.

Polyphen

0.084

B;.

Vest4

0.28

MutPred

0.20

Gain of catalytic residue at P22 (P = 0.0193);Gain of catalytic residue at P22 (P = 0.0193);

MVP

0.56

MPC

0.94

ClinPred

0.87

GERP RS

4.2

PromoterAI

0.014

Neutral

(source)

Varity_R

0.065

gMVP

0.092

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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